Compounds Which Have Activity at M1 Receptor and Their Uses in Medicine

ABSTRACT

Compounds of formula (I) or a salt thereof are provided: 
     
       
         
         
             
             
         
       
     
     wherein R 4 , R 5 , R 6 , Q, A, Y and R are as defined in the description. Uses of the compounds as medicaments and in the manufacture of medicaments for treating psychotic disorders, cognitive impairments and Alzheimer&#39;s Disease are disclosed. The invention further discloses pharmaceutical compositions comprising the compounds.

CROSS REFERENCE TO PRIOR APPLICATIONS

This application is a Divisional of application Ser. No. 12/678,347filed Mar. 16, 2010 which is a 371 National Phase Entry of ApplicationNo. PCT/EP2008/062400 filed 18 Sep. 2008, which claims the priority ofGB 0718419.5, filed 20 Sep. 2007 and GB0814903.1 filed 14 Aug. 2008.

This invention relates to novel compounds, pharmaceutical compositionscontaining them and their use in therapy, in particular as antipsychoticagents, as agents for the treatment of cognitive impairment associatedwith schizophrenia, and as agents for treatment of Alzheimer's Disease.

Muscarinic acetylcholine receptors are members of the G protein-coupledreceptor superfamily which mediate the actions of the neurotransmitteracetylcholine in both the central and peripheral nervous system. Fivemuscarinic receptor subtypes have been cloned, M₁ to M₅. The muscarinicM₁ receptor is predominantly expressed in the cerebral cortex andhippocampus, although it is also expressed in the periphery e.g.exocrine glands.

Muscarinic receptors in the central nervous system, especially M₁, playa critical role in mediating higher cognitive processing. Diseasesassociated with cognitive impairments, such as Alzheimer's Disease, areaccompanied by loss of cholinergic neurons in the basal forebrain.Furthermore, in animal models, blockade or lesion of central cholinergicpathways results in profound cognitive deficits.

Cholinergic replacement therapy has largely been based on the use ofacetylcholinesterase inhibitors to prevent the breakdown of endogenousacetylcholine. These compounds have shown efficacy versus symptomaticcognitive decline in the clinic, but give rise to side effects resultingfrom stimulation of peripheral muscarinic receptors including disturbedgastrointestinal motility and nausea.

The dopamine hypothesis of schizophrenia suggests that excessdopaminergic stimulation is responsible for the positive symptoms of thedisease, hence the utility of dopamine receptor antagonists to reducepsychotic symptoms. However, conventional dopamine receptor antagonistscan cause extrapyramidal side effects (EPS) in patients, includingtremor and tardive dyskinesias.

M₁ receptor agonists have been sought for the symptomatic treatment ofcognitive decline. More recently, a number of groups have shown thatmuscarinic receptor agonists display an atypical antipsychotic-likeprofile in a range of pre-clinical paradigms. The muscarinic agonist,xanomeline, reverses a number of dopamine driven behaviours, includingamphetamine induced locomotion in rats, apomorphine induced climbing inmice, dopamine agonist driven turning in unilateral 6-OH-DA lesionedrats and amphetamine-induced motor unrest in monkeys (without EPSliability). It also has been shown to inhibit A10, but not A9, dopaminecell firing and conditioned avoidance and induces c-fos expression inprefrontal cortex and nucleus accumbens, but not in striatum in rats.These data are all suggestive of an atypical antipsychotic-like profile.

Xanomeline has also been shown to reduce psychotic symptoms such assuspiciousness, hallucinations and delusions in Alzheimer's patients andhas subsequently been assessed in a small phase II trial inschizophrenic patients where it showed a trend to improvement in PANSSand separation from placebo in a cognitive readout. However, therelatively non-selective nature of the compound gives rise todose-limiting peripheral cholinergic side effects.

Over-production of β amyloid is a critical pathogenic event inAlzheimer's Disease (AD) and data have been published showing that M₁receptor agonists modulate the processing of β-APP, the precursor of βamyloid, to increase the production of sAPPa (non-amyloidogenic).Subsequent studies have demonstrated that this event is accompanied by adecreased secretion of β amyloid (for review see Current Opinion inInvestigational Drugs, 2002, 3 (11), 1633-1636). In addition, it hasrecently been reported that an M₁ receptor agonist can affect APPprocessing toward the non-amyloidogenic pathway, in vivo (Neuron, 2006,49, 671-682). Thus M₁ selective agonists have potential for apreventative/disease modifying role in AD therapy.

Certain M₁ receptor agonists are known, for example inPCT/EP2007/052640. We have now found a novel group of compounds whichare M₁ receptor agonists.

In a first aspect therefore, the invention provides a compound offormula (I) or a salt thereof:

wherein:

-   -   R⁴, R⁵ and R⁶ are independently selected from hydrogen, halogen,        C₁₋₆alkyl, C₁₋₆alkyl substituted with one or more fluorine        atoms, cyano, C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfonyl substituted        with one or more fluorine atoms, C₃₋₆cycloalkyl, C₁₋₆alkoxy,        C₁₋₆alkoxy substituted with one or more fluorine atoms,        C₁₋₆alkanoyl, —C(═NOC₁₋₆alkyl)C₁₋₆alkyl, —C₁₋₆alkoxyC₁₋₆alkyl,        and —C(O)NR_(a)R_(b);    -   R_(a) and R_(b) are each independently H or C₁₋₆ alkyl, or        together with the nitrogen atom to which they are attached form        a five or six membered ring;    -   ring A represents a benzene ring, or a 6-membered aromatic        heterocylic ring containing one or two nitrogen atoms;    -   R is selected from C₁₋₆alkyl, C₃₋₆cycloalkyl,        C₃₋₆cycloalkylC₁₋₄alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,        C₃₋₆cycloalkyloxyC₁₋₆alkyl and        C₃₋₆cycloalkylC₁₋₄alkyloxyC₁₋₆alkyl, wherein any alkyl or        cycloalkyl group is optionally substituted by one or more        fluorine atoms;    -   Q is selected from hydrogen and C₁₋₆alkyl; and    -   Y is selected from O, S, CH₂ optionally substituted with one or        two fluorine atoms or optionally substituted with one or two        methyl groups, CH₂CH₂, OCH₂, and CH₂O.

As used herein, the term “alkyl” refers to a straight or branchedhydrocarbon chain containing the specified number of carbon atoms. Forexample, “C₁₋₆alkyl” means a straight or branched alkyl containing atleast 1, and at most 6, carbon atoms. Examples of “C₁₋₆alkyl” include,but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl,n-hexyl, isobutyl, isopropyl, t-butyl and 1,1-dimethylpropyl “C₁₋₄alkyl”means a straight or branched alkyl containing at least 1, and at most 4,carbon atoms. Examples of “C₁₋₄alkyl” include, but are not limited to,methyl, ethyl, n-propyl, n-butyl, isobutyl, isopropyl, and t-butyl.

As used herein, the term “alkoxy” refers to the group “O-alkyl” where“alkyl” is as hereinbefore defined. For example, “C₁₋₆alkoxy” means astraight or branched alkoxy group containing at least 1, and at most 6,carbon atoms. Examples of “C₁₋₆alkoxy” as used herein include, but arenot limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy,1-methylethyl-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy orhexyloxy.

As used herein, the term “cycloalkyl” refers to a non-aromatichydrocarbon ring containing the specified number of carbon atoms. Forexample, “C₃₋₆cycloalkyl” means a non-aromatic carbocyclic ringcontaining at least three, and at most six, ring carbon atoms. Examplesof “C₃₋₆cycloalkyl” as used herein include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term “halogen” (or the abbreviated form “halo”)refers to the elements fluorine (which may be abbreviated to “fluoro” or“F”), chlorine (which may be abbreviated to “chloro” or “Cl”), bromine(which may be abbreviated to “bromo” or “Br”) and iodine (which may beabbreviated to “iodo” or “I”). Examples of halogens are fluorine,chlorine and bromine.

As used herein, the term “C₁₋₆alkylsulfonyl” refers to a groupSO₂—C₁₋₆alkyl, wherein C₁₋₆alkyl is as hereinbefore defined. Examples of“C₁₋₆alkylsulfonyl” as used herein include, but are not limited to,methylsulphonyl, ethylsulphonyl, propylsulphonyl, butylsulphonyl,pentylsulphonyl and hexylsulphonyl.

As used herein, the term “C₁₋₆alkanoyl” refers to a group —C(O)C₁₋₆alkylwherein C₁₋₆alkyl is as hereinbefore defined. Examples of “C₁₋₆alkanoyl”as use herein include, but are not limited to, methanoyl, ethanoyl,propanoyl, butanoyl, pentanoyl and hexanoyl.

As used herein, the term “C₁₋₆alkoxyC₁₋₆alkyl” refers to a groupC₁₋₆alkyl-O—C₁₋₆alkyl wherein C₁₋₆alkyl is as hereinbefore defined.Examples of “C₁₋₆alkoxyC₁₋₆alkyl” as used herein include, but are notlimited to, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl,methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl,ethoxybutyl, ethoxypentyl, and ethoxyhexyl.

As used herein, the term “C₃₋₆cycloalkylC₁₋₄alkyl” refers to a groupC₃₋₆cycloalkly-C₁₋₄alkyl wherein C₃₋₆cycloalkyl and C₁₋₄alkyl are ashereinbefore defined. Examples of “C₃₋₆cycloalkylC₁₋₄alkyl” as usedherein include, but are not limited to, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl,cyclobutylethyl, cyclopentylethyl, and cyclohexylethyl.

As used herein, the term “C₃₋₆cycloalkyloxyC₁₋₆alkyl” refers to a groupC₃₋₆cycloalkyl-O—C₁₋₆alkyl wherein C₃₋₆cycloalkyl and C₁₋₆alkyl are ashereinbefore defined. Examples of “C₃₋₆cycloalkyloxyC₁₋₆alkyl” as usedherein include, but are not limited to cyclopropyloxymethyl,cyclobutyloxymethyl, cyclopentyloxymethyl, cyclohexyloxymethyl,cyclopropyloxyethyl, cyclobutyloxyethyl, cyclopentyloxyethyl, andcyclohexyloxyethyl.

As used herein, the term “C₃₋₆cycloalkylC₁₋₆alkyloxyC₁₋₆alkyl” refers toa group C₃₋₆cycloalkyl-C₁₋₄alkyl-O—C₁₋₆alkyl wherein C₃₋₆cycloalkyl,C₁₋₄alkyl and C₁₋₆alkyl are as hereinbefore defined. Examples of“C₃₋₆cycloalkylC₁₋₄alkyloxyC₁₋₆alkyl” as used herein include, but arenot limited to, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl,cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl,cyclopropylethyloxymethyl, cyclobutylethyloxymethyl,cyclopentylethyloxymethyl, and cyclohexylethyloxymethyl.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated. For example, there may be 1, 2 or3 substituents on a given substituted group. For example, if R⁶ is aC₁₋₆alkyl group, it may be substituted by 1, 2, 3 or 4 fluoro groups;and if R⁶ is a C₁₋₆alkoxy group, it may be substituted by 1, 2, 3 or 4fluoro groups.

In one embodiment, there is provided a compound of formula (I) or a saltthereof, wherein:

-   -   R⁴, R⁵ and R⁶ are independently selected from hydrogen, halogen,        C₁₋₆alkyl, C₁₋₆alkyl substituted with one or more fluorine        atoms, cyano, C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfonyl substituted        with one or more fluorine atoms, C₃₋₆cycloalkyl, C₁₋₆alkoxy,        C₁₋₆alkoxy substituted with one or more fluorine atoms,        C₁₋₆alkanoyl, —C(═NOC₁₋₅alkyl)C₁₋₅alkyl, —C₁₋₄alkoxyC₁₋₄alkyl,        and —C(O)NR_(a)R_(b);    -   R_(a) and R_(b) are each independently H or C₁₋₆ alkyl, or        together with the nitrogen atom to which they are attached form        a five or six membered ring;    -   d ring A represents a benzene ring, or a 6-membered aromatic        heterocylic ring containing one or two nitrogen atoms;    -   R is selected from C₃₋₆cycloalkylC₁₋₄alkyl,        C₃₋₆cycloalkyloxyC₁₋₆alkyl and        C₃₋₆cycloalkylC₁₋₄alkyloxyC₁₋₆alkyl, wherein any alkyl or        cycloalkyl group is optionally substituted by one or more        fluorine atoms;    -   Q is selected from hydrogen and C₁₋₆alkyl; and    -   Y is selected from O, S, CH₂CH₂, OCH₂, and CH₂O.

In one embodiment there is provided a compound of formula (I) or a saltthereof wherein:

-   -   R⁴, R⁵ and R⁶ are independently selected from hydrogen, halogen,        C₁₋₆alkyl, substituted with one or more fluorine atoms, cyano,        C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfonyl substituted with one or        more fluorine atoms, C₃₋₆cycloalkyl, C₁₋₆alkoxy, C₁₋₆alkoxy        substituted with one or more fluorine atoms, C₁₋₆alkanoyl,        —C(═NOC₁₋₅alkyl)C₁₋₅alkyl, —C₁₋₄alkoxyC₁₋₄alkyl, and        —C(O)NR_(a)R_(b);    -   R_(a) and R_(b) are each independently H or C₁₋₆ alkyl, or        together with the nitrogen atom to which they are attached form        a five or six membered ring;    -   ring A represents a benzene ring, or a 6-membered aromatic        heterocylic ring containing one or two nitrogen atoms;    -   R is selected from C₁₋₆alkyl and C₃₋₆cycloalkyl, wherein any        alkyl or cycloalkyl group is optionally substituted by one or        more fluorine atoms;    -   Q is selected from hydrogen and C₁₋₆alkyl; and    -   Y is CH₂ optionally substituted with one or two fluorine atoms        or optionally substituted with one or two methyl groups.

In one embodiment R⁴, R⁵ and R⁶ are independently selected fromhydrogen, halogen, C₁₋₆alkyl optionally substituted with one or morefluorine atoms, cyano, C₁₋₆alkylsulfonyl, CF₃SO₂, C₁₋₆alkoxy optionallysubstituted with one or more fluorine atoms, and C₁₋₄alkoxyC₁₋₄alkyl. Ina further embodiment R⁴, R⁵ and R⁶ are independently selected fromhydrogen, halogen, C₁₋₄alkyl optionally substituted with one or morefluorine atoms, cyano, C₁₋₄alkylsulfonyl, and C₁₋₄alkoxy optionallysubstituted with one or more fluorine atoms. In a further embodiment R⁴,R⁵ and R⁶ are independently selected from hydrogen, halogen, C₁₋₂alkyloptionally substituted with one or more fluorine atoms, cyano,C₁₋₂alkylsulfonyl, and C₁₋₂alkoxy optionally substituted with one ormore fluorine atoms. In a further embodiment R⁴, R⁵ and R⁶ areindependently selected from hydrogen, fluorine, methyl, trifluoromethyl,cyano, methylsulfonyl, ethylsulfonyl, methoxy, difluoromethoxy,trifluoromethoxy, and methoxymethyl.

In one embodiment R⁴ is selected from hydrogen, halogen, C₁₋₆alkyl(optionally substituted with one or more fluorine atoms), cyano,C₁₋₆alkylsulfonyl (optionally substituted with one or more fluorineatoms), C₁₋₆alkoxy (optionally substituted with one or more fluorineatoms), and C₁₋₄alkoxyC₁₋₄alkyl.

In one embodiment R⁴ is selected from hydrogen, halogen, C₁₋₄alkyloptionally substituted with one or more fluorine atoms, cyano,C₁₋₄alkylsulfonyl, and C₁₋₄alkoxy optionally substituted with one ormore fluorine atoms.

In one embodiment R⁴ is selected from hydrogen, halogen, C₁₋₂alkyloptionally substituted with one or more fluorine atoms, cyano,C₁₋₂alkylsulfonyl, and C₁₋₂alkoxy optionally substituted with one ormore fluorine atoms.

In one embodiment R⁴ is selected from hydrogen, fluorine, methyl,trifluoromethyl, cyano, methylsulfonyl, ethylsulfonyl, methoxy,difluoromethoxy, trifluoromethoxy, and methoxymethyl.

In one embodiment R⁴ is hydrogen or fluorine.

In one embodiment, R⁴ is hydrogen.

In one embodiment R⁵ is selected from hydrogen, halogen, C₁₋₆alkyl(optionally substituted with one or more fluorine atoms), cyano,C₁₋₆alkylsulfonyl (optionally substituted with one or more fluorineatoms), C₁₋₆alkoxy (optionally substituted with one or more fluorineatoms), and C₁₋₄alkoxyC₁₋₄alkyl.

In one embodiment R⁵ is selected from hydrogen, halogen, C₁₋₄alkyl(optionally substituted with one or more fluorine atoms), cyano,C₁₋₄alkylsulfonyl, and C₁₋₄alkoxy (optionally substituted with one ormore fluorine atoms).

In one embodiment R⁵ is selected from hydrogen, halogen, C₁₋₂alkyl(optionally substituted with one or more fluorine atoms), cyano,C₁₋₂alkylsulfonyl, and C₁₋₂alkoxy (optionally substituted with one ormore fluorine atoms).

In one embodiment R⁵ is selected from hydrogen, fluorine, methyl,trifluoromethyl, cyano, methylsulfonyl, ethylsulfonyl, methoxy,difluoromethoxy, trifluoromethoxy, and methoxymethyl.

In one embodiment, R⁵ is selected from hydrogen, fluorine, cyano andmethyl.

In one embodiment, R⁵ is hydrogen.

In one embodiment R⁶ is selected from hydrogen, halogen, C₁₋₆alkyl(optionally substituted with one or more fluorine atoms), cyano,C₁₋₆alkylsulfonyl (optionally substituted with one or more fluorineatoms), C₁₋₆alkoxy (optionally substituted with one or more fluorineatoms), C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₆alkanoyl, —C(═NOC₁₋₅alkyl)C₁₋₅alkyl and—C(O)NR_(a)R_(b).

In one embodiment R⁶ is selected from hydrogen, halogen, C₁₋₄alkyl(optionally substituted with one or more fluorine atoms), cyano,C₁₋₄alkylsulfonyl (optionally substituted with one or more fluorineatoms), C₁₋₄alkoxy (optionally substituted with one or more fluorineatoms), C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkanoyl, —C(═NOC₁₋₄alkyl)C₁₋₄alkyl and—C(O)NR_(a)R_(b).

In one embodiment R⁶ is selected from hydrogen, halogen, C₁₋₂alkyl(optionally substituted with one or more fluorine atoms), cyano,C₁₋₂alkylsulfonyl (optionally substituted with one or more fluorineatoms), C₁₋₂alkoxy (optionally substituted with one or more fluorineatoms), C₁₋₂alkoxyC₁₋₂alkyl, C₁₋₂alkanoyl, —C(═NOC₁₋₂alkyl)C₁₋₂alkyl and—C(O)NR_(a)R_(b).

In one embodiment R⁶ is selected from hydrogen, fluorine, methyl,trifluoromethyl, cyano, methylsulfonyl, ethylsulfonyl,trifluoromethylsulfonyl, methoxy, difluoromethoxy, trifluoromethoxy,—C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃, and methoxymethyl.

In one embodiment R⁶ is selected from hydrogen, methyl, trifluoromethyl,cyano, methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, methoxy,difluoromethoxy, trifluoromethoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃,and methoxymethyl.

In one embodiment, R⁶ is cyano.

In one embodiment ring A represents a benzene ring or a pyridine ring.

In one embodiment ring A represents a benzene ring.

In one embodiment ring A represents a pyridine ring.

In one embodiment, the invention provides a compound of formula (Ia) ora salt thereof:

wherein R⁴, R⁵, R⁶, Y, Q and R are as hereinbefore defined for acompound of formula (I). In one embodiment R is selected fromC₃₋₆cycloalkylC₁₋₄alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₃₋₆cycloalkyloxyC₁₋₆alkyl and C₃₋₆cycloalkylC₁₋₄alkyloxyC₁₋₆alkyl,wherein any alkyl or cycloalkyl group is optionally substituted by oneor more fluorine atoms.

In one embodiment R is selected from C₁₋₆alkyl and C₃₋₆cycloalkyl.

In one embodiment R is selected from C₁₋₆alkyl, C₃₋₆cycloalkylC₁₋₄alkyland C₁₋₆alkyloxyC₁₋₆alkyl.

In one embodiment R is selected from C₁₋₆alkyl, C₃₋₆cycloalkylC₁₋₄alkyland C₁₋₆alkyloxyC₁₋₆alkyl.

In one embodiment R is selected from methyl, ethyl, n-propyl, i-propyl,cyclopropylmethyl and methoxyethyl.

In one embodiment R is selected from C₃₋₆cycloalkylC₁₋₄alkyl andC₁₋₆alkyloxyC₁₋₆alkyl.

In one embodiment R is selected from C₃₋₆cycloalkylC₁₋₄alkyl andC₁₋₄alkyloxyC₁₋₄alkyl.

In one embodiment R is C₁₋₆alkyloxyC₁₋₆alkyl.

In one embodiment R is selected from cyclopropylmethyl and methoxyethyl.

In one embodiment R is methoxyethyl.

In one embodiment Q is selected from the group consisting of H andC₁₋₄alkyl.

In one embodiment, Q is selected from the group consisting of H andC₁₋₂alkyl.

In one embodiment, Q is H or methyl.

In one embodiment, Q is methyl.

In one embodiment, Q is H.

In one embodiment Y is selected from O, OCH₂, CH₂ or CH₂CH₂ and C(CH₃)₂.

In one embodiment Y is selected from O, S, OCH₂, CH₂O and CH₂CH₂.

In one embodiment Y is selected from CH₂ optionally substituted with oneor two fluorine atoms or optionally substituted with one or two methylgroups.

In one embodiment, Y is O.

In one embodiment, there is provided a compound of formula (I) or a saltthereof wherein:

R⁴ is hydrogen or fluorine;

R⁵ is selected from hydrogen, fluorine, cyano and methyl;

R⁶ is selected from hydrogen, fluorine, methyl, trifluoromethyl, cyano,methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, methoxy,difluoromethoxy, trifluoromethoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃,and methoxymethyl;

A is a benzene ring or a pyridine ring;

R is selected from methyl, ethyl, n-propyl, i-propyl, cyclopropylmethyland methoxyethyl;

Q is H or methyl; and

Y is selected from O, OCH₂, CH₂, CH₂CH₂ and C(CH₃)₂.

In one embodiment, there is provided a compound of formula (I) or a saltthereof wherein:

R⁴ is hydrogen or fluorine;

R⁵ is selected from hydrogen, fluorine, cyano and methyl;

R⁶ is selected from hydrogen, methyl, trifluoromethyl, cyano,methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, methoxy,difluoromethoxy, trifluoromethoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃,and methoxymethyl;

A is a benzene ring or a pyridine ring;

R is selected from methyl, ethyl, n-propyl, i-propyl, cyclopropylmethyland methoxyethyl;

Q is H or methyl; and

Y is selected from O, OCH₂, CH₂, CH₂CH₂ and C(CH₃)₂.

In one embodiment, the compound of formula (I) is a compound of formula(Ia) wherein:

R⁴ is hydrogen or fluorine;

R⁵ is selected from hydrogen, fluorine, cyano and methyl;

R⁶ is selected from hydrogen, fluorine, methyl, trifluoromethyl, cyano,methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, methoxy,difluoromethoxy, trifluoromethoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃,and methoxymethyl;

R is selected from methyl, ethyl, n-propyl, i-propyl, cyclopropylmethyland methoxyethyl;

Q is H or methyl; and

Y is selected from O, OCH₂, CH₂, CH₂CH₂ and C(CH₃)₂.

In one embodiment, the compound of formula (I) is a compound of formula(Ia) wherein:

R⁴ is hydrogen or fluorine;

R⁵ is selected from hydrogen, fluorine, cyano and methyl;

R⁶ is selected from hydrogen, methyl, trifluoromethyl, cyano,methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, methoxy,difluoromethoxy, trifluoromethoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃,and methoxymethyl;

R is selected from methyl, ethyl, n-propyl, i-propyl, cyclopropylmethyland methoxyethyl;

Q is H or methyl; and

Y is selected from O, OCH₂, CH₂, CH₂CH₂ and C(CH₃)₂.

In one embodiment, there is provided a compound of formula (I) or a saltthereof wherein:

R⁴ is hydrogen or fluorine;

R⁵ is selected from hydrogen, fluorine, cyano and methyl;

R⁶ is selected from hydrogen, fluorine, methyl, trifluoromethyl, cyano,methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, methoxy,difluoromethoxy, trifluoromethoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃,and methoxymethyl;

A is a benzene ring or a pyridine ring;

R is selected from cyclopropylmethyl and methoxyethyl;

Q is H or methyl; and

Y is selected from O, OCH₂ and CH₂CH₂.

In one embodiment, there is provided a compound of formula (I) or a saltthereof wherein:

R⁴ is hydrogen or fluorine;

R⁵ is selected from hydrogen, fluorine, cyano and methyl;

R⁶ is selected from hydrogen, methyl, trifluoromethyl, cyano,methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, methoxy,difluoromethoxy, trifluoromethoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃,and methoxymethyl;

A is a benzene ring or a pyridine ring;

R is selected from cyclopropylmethyl and methoxyethyl;

Q is H or methyl; and

Y is selected from O, OCH₂ and CH₂CH₂.

In one embodiment, the compound of formula (I) is a compound of formula(Ia) wherein:

R⁴ is hydrogen or fluorine;

R⁵ is selected from hydrogen, fluorine, cyano and methyl;

R⁶ is selected from hydrogen, fluorine, methyl, trifluoromethyl, cyano,methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, methoxy,difluoromethoxy, trifluoromethoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃,and methoxymethyl;

R is selected from cyclopropylmethyl and methoxyethyl;

Q is H or methyl; and

Y is selected from O, OCH₂ and CH₂CH₂.

In one embodiment, the compound of formula (I) is a compound of formula(Ia) wherein:

R⁴ is hydrogen or fluorine;

R⁵ is selected from hydrogen, fluorine, cyano and methyl;

R⁶ is selected from hydrogen, methyl, trifluoromethyl, cyano,methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, methoxy,difluoromethoxy, trifluoromethoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃,and methoxymethyl;

R is selected from cyclopropylmethyl and methoxyethyl;

Q is H or methyl; and

Y is selected from O, OCH₂ and CH₂CH₂.

In one embodiment, the compound of formula (I) is a compound of formula(Ia) wherein:

R⁴ is hydrogen or fluorine;

R⁵ is selected from hydrogen, fluorine and cyano;

R⁶ is selected from methyl, trifluoromethyl, cyano, methylsulfonyl,methoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃, and methoxymethyl;

R is selected from cyclopropylmethyl and methoxyethyl;

Q is H or methyl; and

Y is O.

In one embodiment, the compound of formula (I) is a compound of formula(Ia) wherein:

R⁴ is hydrogen, R⁵ is hydrogen, R⁶ is cyano, R is methoxyethyl, Q ismethyl, and Y is O.

In one embodiment, the invention provides a compound of formula (I′) ora salt or solvate thereof:

wherein

-   -   R⁴, R⁵ and R⁶ are independently selected from hydrogen, halogen,        C₁₋₆alkyl, substituted with one or more fluorine atoms, cyano,        C₁₋₆alkylsulfonyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, and C₁₋₆alkoxy        substituted with one or more fluorine atoms;    -   ring A represents a benzene ring, or a 6-membered aromatic        heterocylic ring containing one or two nitrogen atoms;    -   R is selected from C₁₋₆alkyl, C₃₋₆cycloalkyl,        C₃₋₆cycloalkylC₁₋₄alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,        C₃₋₆cycloalkyloxyC₁₋₆alkyl and        C₃₋₆cycloalkylC₁₋₄alkyloxyC₁₋₆alkyl, wherein any alkyl or        cycloalkyl group is optionally substituted by one or more        fluorine atoms;    -   Q is selected from hydrogen and C₁₋₆alkyl; and    -   Y is selected from O, S, CH₂ optionally substituted with one or        two fluorine atoms, CH₂CH₂, OCH₂, and CH₂O.

It will be appreciated that the present invention covers allcombinations of features and embodiments described hereinbefore.

All features and embodiments for formula (I) apply to compounds offormula (I′) and (Ia) mutatis mutandis. Hereinafter, all references tocompounds of formula (I) include compounds of formula (I′) and (Ia).

In one embodiment the salt of the compound of formula (I) is apharmaceutically acceptable salt. In one embodiment, the inventionprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof.

In one embodiment, the invention provides a compound of formula (I) asthe free base.

It will be appreciated that for use in medicine the salts of formula (I)should be pharmaceutically acceptable. Suitable salts will be apparentto those skilled in the art and include for example mono- or di-basicsalts formed with inorganic acids e.g. hydrochloric, hydrobromic,sulfuric, nitric, sulfamic phosphoric, hydroiodic, phosphoric ormetaphosphoric acid; and with organic acids, such as tartaric, acetic,trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic,propionic, glycolic, gluconic, maleic, succinic,(1R)-(−)-10-camphorsulphonic, (1S)-(+)-10-camphorsulphonic, isothionic,mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic,ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic,sulfinilic, alginic, galacturonic and arylsulfonic, for examplenaphthalene-1,5-disulphonic, naphthalene-1,3-disulphonic,benzenesulfonic, and p-toluenesulfonic, acids. Othernon-pharmaceutically acceptable salts e.g. oxalates, may be used, forexample in the isolation of compounds of formula (I) and are includedwithin the scope of this invention. Certain of the compounds of formula(I) may form acid addition salts with less than one (for example, 0.5equivalent of a dibasic acid) or one or more equivalents of an acid. Thepresent invention includes within its scope all possible stoichiometricand non-stoichiometric forms thereof.

The compounds of the present invention may be in the form of their freebase or pharmaceutically acceptable salts thereof, particularly thehydrochloride, formate, trifluoroacetate, methanesulfonate, or4-methylbenzenesulfonate salts.

In one embodiment, the pharmaceutically acceptable salt is ahydrochloride salt, a trifluoroacetate salt, or a formate salt.

In one embodiment the pharmaceutically acceptable salt is thehydrocholoride salt.

Solvates of the compounds of formula (I) and solvates of the salts ofcompounds of formula (I) are included within the scope of the presentinvention. As used herein, the term “solvate” refers to a complex ofvariable stoichiometry formed by a solute (in this invention, a compoundof formula (I) or a salt thereof) and a solvent. Those skilled in theart of organic chemistry will appreciate that many organic compounds canform such complexes with solvents in which they are reacted or fromwhich they are precipitated or crystallised. Such solvents for thepurpose of the invention may not interfere with the biological activityof the solute. Examples of suitable solvents include, but are notlimited to, water, methanol, ethanol and acetic acid. Preferably thesolvent used is a pharmaceutically acceptable solvent. Examples ofsuitable pharmaceutically acceptable solvents include, withoutlimitation, water, ethanol and acetic acid. Most preferably the solventused is water. Where the solvent used is water such a solvate may thenalso be referred to as a hydrate.

It will be appreciated by those skilled in the art that certainprotected derivatives of compounds of formula (I), which may be madeprior to a final deprotection stage, may not possess pharmacologicalactivity as such, but may, in certain instances, be administered orallyor parenterally and thereafter metabolised in the body to form compoundsof the invention which are pharmacologically active. Such derivativesmay therefore be described as “prodrugs”. Further, certain compounds ofthe invention may act as prodrugs of other compounds of the invention.All protected derivatives and prodrugs of compounds of the invention areincluded within the scope of the invention. Examples of suitableprotecting groups for the compounds of the present invention aredescribed in Drugs of Today, Volume 19, Number 9, 1983, pp 499-538 andin Topics in Chemistry, Chapter 31, pp 306-316 and in “Design ofProdrugs” by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures inwhich documents are incorporated herein by reference). It will furtherbe appreciated by those skilled in the art, that certain moieties, knownto those skilled in the art as “pro-moieties”, for example as describedby H. Bundgaard in “Design of Prodrugs” (the disclosure in whichdocument is incorporated herein by reference) may be placed onappropriate functionalities when such functionalities are present withincompounds of the invention. Possible prodrugs for some compounds of theinvention include: esters, carbonate esters, hemi-esters, phosphateesters, nitro esters, sulfate esters, sulfoxides, amides, carbamates,azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.

The compounds of formula (I) may have the ability to crystallise in morethan one form. This is a characteristic known as polymorphism, and it isunderstood that such polymorphic forms (“polymorphs”) are within thescope of formula (I). Polymorphism generally can occur as a response tochanges in temperature or pressure or both and can also result fromvariations in the crystallisation process. Polymorphs can bedistinguished by various physical characteristics known in the art suchas x-ray diffraction patterns, solubility, and melting point.

Hereinafter, compounds of formula (I) (whether in solvated or unsolvatedform) or their pharmaceutically acceptable salts (whether in solvated orunsolvated form) or prodrugs thereof defined in any aspect of theinvention (except intermediate compounds in chemical processes) arereferred to as “compounds of the invention”.

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine andchlorine such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and³⁶Cl, respectively. Certain isotopic variations of the invention, forexample, those in which a radioactive isotope such as ³H or ¹⁴C isincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated, i.e., ³H, and carbon-14, i.e., isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with isotopes such as deuterium, i.e., ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements and hence may be preferred in some circumstances. Isotopicvariations of the compounds of the invention can generally be preparedby conventional procedures such as by the illustrative methods or by thepreparations described in the Examples hereafter using appropriateisotopic variations of suitable reagents.

It will be appreciated that compounds of formula (I) can exist in cis ortrans isomeric forms (the OR group on the cyclohexane ring in relationto the piperidine substituent).

It will be appreciated that the cis form may be drawn in the followingdifferent ways, although both represent the same isomeric form:

It will be appreciated that the trans form may be drawn in the followingdifferent ways, although both represent the same isomeric form:

The individual isomers (cis and trans) and mixtures of these areincluded within the scope of the present invention. The isomers may beseparated one from the other by the usual methods or by methods detailedfor the example compounds below. Any given isomer may also be obtainedby stereospecific synthesis. The invention also extends to anytautomeric forms and mixtures thereof.

In one embodiment, the compounds of formula (I) are trans isomers.

In another embodiment, the compounds of formula (I) are cis isomers.

Mixtures of cis- and trans-compounds, or compounds in which thecis/trans conformation have not been determined, are drawn herein asshown below:

Compounds according to the invention include:—

-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one;-   3-{1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-fluoro-5-methyl-1,3-benzoxazol-2(3H)-one;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(ethylsulfonyl)-1,3-benzoxazol-2(3H)-one;-   5-Fluoro-3-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-fluoro-1,3-benzoxazol-2(3H)-one;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(methyloxy)-1,3-benzoxazol-2(3H)-one;-   3-{1-[trans-4-(Ethyloxy)cyclohexyl]-4-piperidinyl}-5-methyl-1,3-benzoxazol-2(3H)-one;-   4-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-2H-1,4-benzoxazin-3(4H)-one;-   3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;-   3-[1-(cis-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidnyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;-   6-Methyl-1-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-dihydro-2H-indol-2-one;-   3-{1-[trans-4-Ethoxy-1-methylcyclohexyl]-4-piperidinyl}-7-fluoro-5-methyl-1,3-benzoxazol-2(3H)-one;-   3-{1-[trans-4-Ethoxy-1-methylcyclohexyl]-4-piperidinyl}-6,7-difluoro-5-methyl-1,3-benzoxazol-2(3H)-one;-   5-Methyl-3-{1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5,7-difluoro-1,3-benzoxazol-2(3H)-one;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-[(trifluoromethyl)oxy]-1,3-benzoxazol-2(3H)-one;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5,6-difluoro-1,3-benzoxazol-2(3H)-one;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-one;-   6-Methyl-1-{1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}-1,3-dihydro-2H-indol-2-one;-   3-{1-[trans-1-Methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;-   1-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-1,3-dihydro-2H-indol-2-one;-   3-{1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one;-   1-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-7-methyl-3,4-dihydro-2(1H)-quinolinone;    and salts thereof.

Further compounds according to the invention include:

-   3,3,6-Trimethyl-1-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-dihydro-2H-indol-2-one;-   6-Methyl-1-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidnyl]-1,3-dihydro-2H-indol-2-one;-   3-{1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-5-[(trifluoromethyl)sulfonyl]-1,3-benzoxazol-2(3H)-one;-   6-Methyl-3-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one;-   6-Methyl-5-(methylsulfonyl)-3-{1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one;-   5-Methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbonitrile;-   5-(Difluoromethoxy)-3-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one;-   5-Methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one;-   3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(methyloxy)-1,3-benzoxazol-2(3H)-one;-   3-(1-{trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexyl}-4-piperidinyl)-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one;-   3-(1-{trans-1-Methyl-4-[(1-methylethyl)oxy]cyclohexyl}-4-piperidinyl)-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one;-   3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-one;-   6-Fluoro-5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]-oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one;-   7-Fluoro-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;-   7-Fluoro-5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one;-   6-Fluoro-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;-   3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one;-   3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-[(methyloxy)methyl]-1,3-benzoxazol-2(3H)-one;-   1-[1-(trans-1-Methyl-4-[2-(methoxyethoxy)cyclohexyl]-4-piperidinyl]-6-(methoxymethyl)-1,3-dihydro-2H-indol-2-one;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carboxamide;-   3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carboxamide;-   5-Acetyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one;-   3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-[N-(methyloxy)ethanimidoyl]-1,3-benzoxazol-2(3H)-one;-   1-[1-(trans-4-{2-Methoxyethoxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-d    hydro-1H-indole-6-carbonitrile;-   1-[1-(cis-4-{2-Methoxyethoxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile;-   3-{1-[trans-4-(Ethyloxy)cyclohexyl]-4-piperidinyl}-5-fluoro-1,3-benzoxazol-2(3H)-one;    and-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-methyl[1,3]oxazolo[4,5-b]pyridin-2(3H)-one;    and salts thereof.

In one embodiment, the salt of a compound listed above is apharmaceutically acceptable salt.

In one embodiment, the pharmaceutically acceptable salt is ahydrochloride salt, a trifluoroacetate salt, a methanesulfonate salt, a4-methylbenzenesulfonate salt, or a formate salt.

In one embodiment, the pharmaceutically acceptable salt is ahydrochloride salt, a trifluoroacetate salt, or a formate salt.

In one embodiment the pharmaceutically acceptable salt is thehydrochloride salt.

In one embodiment, the compound of the present invention is selectedfrom:—

-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-1,3-benz    oxazol-2(3H)-one hydrochloride;-   3-{1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile    hydrochloride;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-fluoro-5-methyl-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(ethylsulfonyl)-1,3-benzoxazol-2(3H)-one    hydrochloride;-   5-Fluoro-3-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-fluoro-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(methyloxy)-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-{1-[trans-4-(Ethyloxy)cyclohexyl]-4-piperidinyl}-5-methyl-1,3-benzoxazol-2(3H)-one    hydrochloride;-   4-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-2H-1,4-benzoxazin-3(4H)-one    hydrochloride;-   3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile    hydrochloride;-   3-[1-(cis-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile    hydrochloride;-   6-Methyl-1-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-dihydro-2H-indol-2-one    hydrochloride;-   3-{1-[trans-4-Ethoxy-1-methylcyclohexyl]-4-piperidinyl}-7-fluoro-5-methyl-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-{1-[trans-4-Ethoxy-1-methylcyclohexyl]-4-piperidinyl}-6,7-difluoro-5-methyl-1,3-benzoxazol-2(3H)-one    hydrochloride;-   5-Methyl-3-{1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5,7-difluoro-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-[(trifluoromethyl)oxy]-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5,6-difluoro-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-one    hydrochloride;-   6-Methyl-1-{1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}-1,3-dihydro-2H-indol-2-one    hydrochloride;-   3-{1-[trans-1-Methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile    hydrochloride;-   1-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-1,3-dihydro-2H-indol-2-one    hydrochloride;-   3-{1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one    hydrochloride; and-   1-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-7-methyl-3,4-dihydro-2(1H)-quinolinone.

In one embodiment, the compound of the present invention is selectedfrom:—

-   3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;-   3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile    hydrochloride;-   3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile    4-methylbenzenesulfonate; and-   3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile    methanesulfonate.

In one embodiment, the compound of the present invention is selectedfrom:—

-   3,3,6-Trimethyl-1-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-dihydro-2H-indol-2-one    hydrochloride;-   6-Methyl-1-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidnyl]-1,3-dihydro-2H-indol-2-one    hydrochloride;-   3-{1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-5-[(trifluoromethyl)sulfonyl]-1,3-benzoxazol-2(3H)-one    hydrochloride;-   6-Methyl-3-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one    hydrochloride;-   6-Methyl-5-(methylsulfonyl)-3-{1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one    hydrochloride;-   5-Methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbonitrile    hydrochloride;-   5-(Difluoromethoxy)-3-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one    hydrochloride;-   5-Methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(methyloxy)-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-(1-{trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexyl}-4-piperidinyl)-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-(1-{trans-1-Methyl-4-[(1-methylethyl)oxy]cyclohexyl}-4-piperidinyl)-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-one    hydrochloride;-   6-Fluoro-5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]-oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one    hydrochloride;-   7-Fluoro-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile    hydrochloride;-   7-Fluoro-5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one    hydrochloride;-   6-Fluoro-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile    hydrochloride;-   3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-[(methyloxy)methyl]-1,3-benzoxazol-2(3H)-one    hydrochloride;-   1-[1-(trans-1-Methyl-4-[2-(methoxyethoxy)cyclohexyl]-4-piperidinyl]-6-(methoxymethyl)-1,3-dihydro-2H-indol-2-one;-   1-[1-(trans-1-Methyl-4-[2-(methoxyethoxy)cyclohexyl]-4-piperidinyl]-6-(methoxymethyl)-1,3-dihydro-2H-indol-2-one    hydrochloride;-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carboxamide    hydrochloride;-   3-[1-(trans-1-Methyl-4-[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carboxamide    hydrochloride;-   5-Acetyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one    hydrochloride;-   3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-[N-(methyloxy)ethanimidoyl]-1,3-benzoxazol-2(3H)-one    hydrochloride;-   1-[1-(trans-4-{2-Methoxyethoxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile;-   1-[1-(cis-4-{2-Methoxyethoxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile;-   3-{1-[trans-4-(Ethyloxy)cyclohexyl]-4-piperidinyl}-5-fluoro-1,3-benzoxazol-2(3H)-one;    and-   3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-methyl[1,3]oxazolo[4,5-b]pyridin-2(3H)-one    hydrochloride.

In one embodiment, the compound of the present invention is selectedfrom3-[1-(1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrileand pharmaceutically acceptable salts thereof.

In one embodiment, the compound of the present invention is selectedfrom3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrileand pharmaceutically acceptable salts thereof.

In one embodiment, the compound of the present invention is3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile.

In one embodiment, the compound of the present invention is3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilehydrochloride.

In a further aspect, the invention provides a general process (A1) forpreparing compounds of formula (I) in which Q=H, which processcomprises:

coupling a compound of formula (II):

with a compound of formula (III)

wherein R^(6′) is a group R⁶ as previously defined, or a groupconvertible to R⁶, R^(5′) is a group R⁵ as previously defined, or agroup convertible to R⁵, R^(4′) is a group R⁴ as previously defined, ora group convertible to R⁴, ring A is as previously defined, R′ is agroup R as previously defined, or a group convertible to R, and Y is O,S, CH₂ optionally substituted with one or two fluorine atoms, CH₂optionally substituted with one or two methyl groups, CH₂CH₂, OCH₂, orCH₂O.

The reaction is carried out under conditions suitable for reductivealkylation. The reductive alkylation reaction is typically carried outusing sodium triacetoxyborohydride in dichloroethane, optionally in thepresence of triethylamine, and optionally in the presence of titaniumtetraisopropoxide. Alternatively sodium cyanoborohydride can be used asthe reducing reagent in solvents such as methanol or ethanol, or thereductive alkylation can be effected under catalytic hydrogenationconditions using a palladium catalyst. In a further variation, thecompounds (II) and (III) can be condensed under dehydrating conditionse.g. molecular sieves or magnesium sulfate, and the resultant imine orenamine reduced using for example sodium borohydride or by catalytichydrogenation.

This reaction can generate a mixture of cis and trans isomers which canbe separated, for example, by chromatography or crystallisation.

A modification of general process (A1) is required where Q is C₁₋₆alkyl.Thus, in general process (A2), a compound of formula (II) can be reactedwith a compound of formula (III) in the presence of a source of cyanide,e.g. acetone cyanohydrin, to form the cyano intermediate (IV) which canbe reacted with an alkyl Grignard reagent QMgX to form compounds offormula (I) in which Q is C₁₋₆alkyl.

wherein R^(6′) is a group R⁶ as previously defined, or a groupconvertible to R⁶, R^(5′) is a group R⁵ as previously defined, or agroup convertible to R⁵, R^(4′) is a group R⁴ as previously defined, ora group convertible to R⁴, ring A is as previously defined, R′ is agroup R as previously defined, or a group convertible to R, Y is O, S,CH₂ optionally substituted with one or two fluorine atoms, CH₂optionally substituted with one or two methyl groups, CH₂CH₂, OCH₂, orCH₂O, Q is C₁₋₆alkyl, and X is bromo or iodo or chloro.

This reaction can generate a mixture of cis and trans isomers which canbe separated, for example, by chromatography or crystallisation.

In a further aspect, the invention provides a general process (B) forpreparing compounds of formula (I) in which Y═O or S, which processcomprises:

coupling a compound of formula (V)

with a compound of formula (VI)

wherein R^(6′) is a group R⁶ as previously defined, or a groupconvertible to R⁶, R^(5′) is a group R⁵ as previously defined, or agroup convertible to R⁵, R^(4′) is a group R⁴ as previously defined, ora group convertible to R⁴, ring A is as previously defined, R′ is agroup R as previously defined, or a group convertible to R, Y is O or S,Q is as previously defined, and X and X′ both represent leaving groups.X and X′ can be the same or different and examples are Cl, PhO, EtO, andimidazole. When X and X′ are both Cl, i.e. (VI) is phosgene, thisreagent can be generated in situ e.g. from diphosgene or triphosgene.

The above reaction can be carried out using standard methodology e.g.reacting the amine (V) with the reagent (VI) in an inert solvent forexample dichloromethane or toluene, optionally in the presence of a basesuch as triethylamine or potassium carbonate, and optionally withheating.

It will be appreciated that compounds of formula (V) can be pure cis ortrans isomers, or a mixture of isomers. If necessary, separation of purecis and trans isomers after the reaction with (VI) can be achieved bychromatography or crystallisation.

In a further aspect, the invention provides a general process (C) forpreparing compounds of formula (I) in which Y═CH₂, which processcomprises hydrolysis, decarboxylation and cyclisation of a compound offormula (VII):

wherein R^(6′) is a group R⁶ as previously defined, or a groupconvertible to R⁶, R^(5′) is a group R⁵ as previously defined, or agroup convertible to R⁵, R^(4′) is a group R⁴ as previously defined, ora group convertible to R⁴, ring A is as previously defined, R′ is agroup R as previously defined, or a group convertible to R, Y′ is CH, Qis as previously defined, and R⁷ represents C₁₋₆alkyl, benzyl, or otheracid protecting group; using conditions similar to those described inTet Lett 2001, 42, 6943.

It will be appreciated that compounds of formula (VII) can be pure cisor trans isomers, or a mixture of isomers. If necessary, separation ofpure cis and trans isomers after the cyclisation of (VII) can beachieved by chromatography or crystallisation.

In a further aspect, the invention provides a general process (D) forpreparing compounds of formula (I) in which Y═CH₂CH₂, which processcomprises:

hydrolysis and cyclisation of a compound of formula (VIII)

wherein R^(6′) is a group R⁶ as previously defined, or a groupconvertible to R⁶, R^(5′) is a group R⁵ as previously defined, or agroup convertible to R⁵, R^(4′) is a group R⁴ as previously defined, ora group convertible to R⁴, ring A is as previously defined, R′ is agroup R as previously defined, or a group convertible to R, Q is aspreviously defined, and R⁷ represents C₁₋₆alkyl, benzyl, or other acidprotecting group. Hydrolysis of the ester group CO₂R₇ can beaccomplished using standard conditions, and cyclisation can be effectedby activation of the acid group using for example EDC(1-ethyl-3-(dimethylaminopropyl)carbodiimide) and HOBT(1-hydroxybenzotriazole).

It will be appreciated that compounds of formula (VIII) can be pure cisor trans isomers, or a mixture of isomers. If necessary, separation ofpure cis and trans isomers after the cyclisation of (VIII) can beachieved by chromatography or crystallisation.

In a further aspect, the invention provides a general process (E) forpreparing compounds of formula (I) in which Y═OCH₂, which processcomprises:

treatment of a compound of formula (IX) with a base, such as KO^(t)Bu inan inert solvent for example THF, optionally with heating

wherein R^(6′) is a group R⁶ as previously defined, or a groupconvertible to R⁶, R^(5′) is a group R⁵ as previously defined, or agroup convertible to R⁵, R^(4′) is a group R⁴ as previously defined, ora group convertible to R⁴, ring A is as previously defined, R′ is agroup R as previously defined, or a group convertible to R, Q is aspreviously defined, and Z is a leaving group such as bromo or chloro.

It will be appreciated that compounds of formula (IX) can be pure cis ortrans isomers, or a mixture of isomers. If necessary, separation of purecis and trans isomers after the cyclisation of (IX) can be achieved bychromatography or crystallisation.

In a further aspect, the invention provides a general process (F) forpreparing compounds of formula (I) which process comprises:

treatment of a compound of formula (X)

with a palladium or copper catalyst to effect an intramolecularcyclisation; wherein R^(6′) is a group R⁶ as previously defined, or agroup convertible to R⁶, R^(5′) is a group R⁵ as previously defined, ora group convertible to R⁵, R^(4′) is a group R⁴ as previously defined,or a group convertible to R⁴, ring A is as previously defined, R′ is agroup R as previously defined, or a group convertible to R, Y is O, S,CH₂ optionally substituted with one or two fluorine atoms, CH₂optionally substituted with one or two CH₃ groups, CH₂CH₂, OCH₂, orCH₂O, Q is as previously defined, and Z is a leaving group such asbromo, iodo, chloro or triflate.

The cyclisation reaction can be carried out using a variety of palladiumor copper reagents as described in the literature (JACS, 2003, 125,6653; Tet. Lett., 2004, 45, 8535; or JACS, 2002, 124, 7421.)

It will be appreciated that compounds of formula (X) can be pure cis ortrans isomers, or a mixture of isomers. If necessary, separation of purecis and trans isomers after the intramolecular cyclisation can beachieved by chromatography or crystallisation.

In a further aspect, the invention provides a general process (G) forpreparing compounds of formula (I) which process comprises:

coupling a compound of formula (XIII):

with a compound of formula (XIV)

wherein R^(6′) is a group R⁶ as previously defined, or a groupconvertible to R⁶, R^(5′) is a group R⁵ as previously defined, or agroup convertible to R⁵, R^(4′) is a group R⁴ as previously defined, ora group convertible to R⁴, ring A is as previously defined, R′ is agroup R as previously defined, or a group convertible to R, Y is O, S,CH₂ optionally substituted with one or two fluorine atoms, CH₂optionally substituted with one or two CH₃ groups, CH₂CH₂, OCH₂, orCH₂O, Q is as previously defined, and Z is hydroxy or a leaving groupsuch as chloro, bromo or iodo, or alkyl/aryl sulfonate.

The alkylation reaction can be carried out under classical alkylation(Z=a leaving group) or Mitsunobu reaction (Z═OH) conditions. Usingclassical alkylation conditions, the intermediate (XIII) can bedeprotonated using a base such as sodium hydride in an inert solventsuch as dimethylformamide, and then treated with the alkylating reagent(XIV), optionally with heating. The Mitsunobu reaction with (XIII) and(XIV) Z═OH can be carried out using standard conditions e.g.triphenylphosphine and diethylazodicarboxylate in an inert solvent suchas dichloromethane or tetrahydrofuran at room temperature.

It will be appreciated that compounds of formula (XIV) can be pure cisor trans isomers, or a mixture of isomers. If necessary, separation ofpure cis and trans isomers after the displacement reaction can beachieved by chromatography or crystallisation.

Conversion of R^(6′), R^(5′) and R^(4′) to R⁶, R⁵ and R⁴ respectively,or interconversions of R⁶, R⁵ and R⁴ may be accomplished as illustratedbelow for R^(6′)

For example, when R^(6′) is a halogen, it can be converted to an alkoxy,trifluoromethyl or methylsulphonyl group by copper catalysed reaction,using an alcohol, methyl fluorosulfonyl(difluoro)acetate or sodiummethanesulphinate respectively. It may also be converted to an alkylgroup with an organometallic reagent, for example an alkylstannane.

Alternatively, when R^(6′) is a halogen, it can also be converted to acyano group, for example, by palladium catalysed reaction using zinccyanide.

As another example, when R^(6′) is hydroxy, it may be converted toalkoxy by reaction with an alkyl halide or sulfonate, or totrifluoromethoxy by conversion to the xanthate followed by oxidation inthe presence of fluoride ion.

As a further example, when R^(6′) is methyl, it may be converted totrifluoromethyl by chlorination or bromination followed by displacementof the introduced halogens with fluoride.

Conversion of R′ to R or interconversions of R may be accomplished asindicated below.

For example when R′ is benzyl, the benzyl group can be removed usingstandard methodology, e.g. catalytic hydrogenation over palladium oncarbon, to provide the alcohol. Alkylation of the resultant alcoholusing a strong base e.g. sodium hydride and a C₁₋₆ alkylating agent e.g.methyl iodide, ethyl iodide or propyl iodide, will afford the desiredproduct.

As another example, when R is methyl, the methyl group can be removed bytreatment with a dealkylating agent such as boron tribromide to affordthe alcohol intermediate, which can be alkylated in a similar manner tothat described above. Alternatively the alcohol intermediate can beconverted to R=trifluoromethyl by conversion to the xanthate followed byoxidation in the presence of fluoride ion.

Conversion of compounds wherein Y═CH₂ to compounds wherein Y═C(Me)₂ canbe achieved by treatment of the Y═CH₂ compound with strong base e.g.sodium hydride in an inert solvent e.g. DMF, followed by addition ofexcess methyl iodide.

Compounds of formula (II) are generally known in the literature or canbe prepared by a range of different processes, for example:

(a) reductive amination of the amine (XV) with the ketone (XVI), whereinR^(6′) is a group R⁶ as previously defined, or a group convertible toR⁶, R^(5′) is a group R⁵ as previously defined, or a group convertibleto R⁵, R^(4′) is a group R⁴ as previously defined, or a groupconvertible to R⁴, ring A is as previously defined, Y′ is a group OH orSH or a group convertible to Y′, and P represents a nitrogen protectinggroup (e.g. Boc, acetyl, trifluoroacetyl, ethoxycarbonyl,benzyloxycarbonyl), to give (XVII), followed by deprotection of Y′ ifnecessary, and cyclisation using phosgene or a phosgene equivalent, anddeprotection of the piperidine nitrogen using standard literatureconditions (Scheme 1).

Compounds of formula (XV) are commercially available or can be preparedby standard methodology. The compound (XVI) in which P=Boc iscommercially available.

(b) metal catalysed cyclisation of an intermediate (XVIII) followed bydeprotection of the piperidine nitrogen, wherein R^(6′) is a group R⁶ aspreviously defined, or a group convertible to R⁶, R^(5′) is a group R⁵as previously defined, or a group convertible to R⁵, R^(4′) is a groupR⁴ as previously defined, or a group convertible to R⁴, ring A is aspreviously defined, Y is O, S, CH₂ optionally substituted with one ortwo fluorine atoms, CH₂CH₂, OCH₂, or CH₂O, P represents a nitrogenprotecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl),and Z represents a leaving group such as bromo, iodo, chloro ortriflate. Reaction conditions for the metal catalysed cyclisation aresummarised in Process F. The carbamate, thiocarbamate or amideintermediate (XVIII) can be prepared using any of the classical methodsfor formation of this functionality as illustrated in Scheme 2.Compounds of formula (XIX) and (XI) are commercially available or can beprepared by known methodology. The compound (XX) in which P=Boc iscommercially available. The compound (LX) can be prepared fromN-protected piperidine-4-carboxylic acid, for example by Curtiusrearrangement using diphenylphosphoryl azide.

(c) metal catalysed reaction between the amine (XX) and a suitablysubstituted aromatic compound (XXI) wherein R^(6′) is a group R⁶ aspreviously defined, or a group convertible to

R⁶, R^(5′) is a group R⁵ as previously defined, or a group convertibleto R⁵, R^(4′) is a group R⁴ as previously defined, or a groupconvertible to R⁴, ring A is as previously defined, Y′ is OH or SH or agroup convertible to Y′, P represents a nitrogen protecting group (e.g.Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl), and Z represents aleaving group such as bromo, iodo, chloro or triflate (Scheme 3). Thisprocess generates intermediates of formula (XXII) and subsequentreactions are similar to that for Scheme 1. Compounds of formula (XXI)are commercially available or can be prepared by known methodology. Thecompound (XX) in which P=Boc is commercially available.

(d) alkylation of the heterocycle (XIII) with the intermediate (XXIII)wherein R^(6′) is a group R⁶ as previously defined, or a groupconvertible to R⁶, R⁵ is a group R⁵ as previously defined, or a groupconvertible to R⁵, R^(4′) is a group R⁴ as previously defined, or agroup convertible to R⁴, ring A is as previously defined, Y is O, S orCH₂ optionally substituted with one or two fluorine atoms, P representsa nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl,benzyloxycarbonyl), and Z represents a leaving group such as bromo,iodo, chloro, or mesylate, to give the intermediate (XXIV), followed bydeprotection of the piperidine nitrogen (Scheme 4). Compounds of formula(XIII) are commercially available or can be prepared by knownmethodology. Compounds of formula (XXIII) are commercially available, orcan be prepared using standard literature methodology.

Compounds of formula (III) can be prepared by standard literaturemethodology.

Compounds of formula (V) can be prepared by a number of differentprocesses e.g.:

(e) metal catalysed reaction of the amine (XXV) with the orthosubstituted aromatic compound (XXI), wherein R^(6′) is a group R⁶ aspreviously defined, or a group convertible to R⁶, R^(5′) is a group R⁵as previously defined, or a group convertible to R⁵, R^(4′) is a groupR⁴ as previously defined, or a group convertible to R⁴, ring A is aspreviously defined, Y′ is OH or SH or a group convertible to Y′, R′ is agroup R as previously defined, or a group convertible to R, Q is aspreviously defined, and Z represents a leaving group such as bromo,iodo, chloro or triflate (Scheme 5) followed by deprotection of Y′ ifrequired. Compounds of formula (XXI) are commercially available or canbe prepared by standard methodology. Compounds of formula (XXV) can beprepared as shown in Schemes 12, 13, 14 and 15.

It will be appreciated that compounds of formula (XXV) can be pure cisor trans isomers, or a mixture of isomers. If necessary, separation ofpure cis and trans isomers after the reaction with (XXI) can be achievedby chromatography or crystallisation.

(f) Reductive alkylation of the amine (XV) with the piperidone (XXVI)wherein R^(6′) is a group R⁶ as previously defined, or a groupconvertible to R⁶, R^(5′) is a group R⁵ as previously defined, or agroup convertible to R⁵, R^(4′) is a group R⁴ as previously defined, ora group convertible to R⁴, ring A is as previously defined, Y′ is OH orSH or a group convertible to Y′, R′ is a group R as previously defined,or a group convertible to R, and Q is as previously defined, using forexample sodium triacetoxyborohydride in dichloroethane to give theintermediate (XXVII), followed by deprotection of Y′ if required (Scheme6). Compounds of formula (XXVI) can be prepared as shown in Schemes 13,14 and 15. It will be appreciated that compounds of formula (XXVI) canbe pure cis or trans isomers, or a mixture of isomers. If necessary,separation of pure cis and trans isomers after the reaction with (XV)can be achieved by chromatography or crystallisation.

Compounds of formula (VI) are commercially available e.g. carbonyldiimidazole, phosgene, diphosgene, triphosgene, phenyl chloroformate,diethyl carbonate.

Compounds of formula (VII) in which Y′ is CH can be prepared asillustrated in Scheme 7.

Displacement of Z from the substituted nitro compound (XXVIII) with themalonate (XXIX) wherein R^(6′) is a group R⁶ as previously defined, or agroup convertible to R⁶, R^(6′) is a group R⁵ as previously defined, ora group convertible to R⁵, R^(4′) is a group R⁴ as previously defined,or a group convertible to R⁴, ring A is as previously defined, and R⁷ isa C₁₋₆alkyl or arylalkyl group, using standard conditions for aromaticnucleophilic substitution (Scheme 7) to give (XXX), followed byreduction of the nitro group, and reductive alkylation of the resultantamine (XXXI) with the ketone (XXVI) wherein R′ is a group R aspreviously defined, or a group convertible to R, and Q is as previouslydefined. Compounds of formula (XXVIII) are commercially available, orcan be prepared using standard literature methodology. Compounds offormula (XXIX) are commercially available.

It will be appreciated that compounds of formula (XXVI) can be pure cisor trans isomers, or a mixture of isomers. If necessary, separation ofpure cis and trans isomers after the reaction with (XXXI) can beachieved by chromatography or crystallisation.

Compounds of formula (VIII) can be prepared as illustrated in Scheme 8.

Wittig-Horner reaction of the aldehyde (XXXII) with the appropriatephosphono acetate (XXXIIb) using standard conditions provides thecinnamate (XXXIII). Reduction of the nitro group and double bond leadingto the amine (XXXIV), can be followed by reductive alkylation withketone (XXVI) to give amine (VIII) (Scheme 8), wherein R^(6′) is a groupR⁶ as previously defined, or a group convertible to R⁶, R^(5′) is agroup R⁵ as previously defined, or a group convertible to R⁵, R^(4′) isa group R⁴ as previously defined, or a group convertible to R⁴, ring Ais as previously defined, R′ is a group R as previously defined, or agroup convertible to R, and Q is as previously defined, and R⁷ is aC₁₋₆alkyl group or other acid protecting group. Compounds of formula(XXXII) are commercially available, or can be prepared using standardliterature methodology. Compounds of formula (XXXIIb) are commercviallyavailable.

It will be appreciated that compounds of formula (XXVI) can be pure cisor trans isomers, or a mixture of isomers. If necessary, separation ofpure cis and trans isomers after the reaction with (XXXIV) can beachieved by chromatography or crystallisation.

Compounds of formula (IX) can be prepared as illustrated in Scheme 9.

Reductive alkylation of the amine (XXXV) with the ketone (XXVI) providesthe intermediate (XXXVI), which can then be acylated with theappropriate acid chloride, using standard alkylation conditions to give(IX), wherein R^(6′) is a group R⁶ as previously defined, or a groupconvertible to R⁶, R^(5′) is a group R⁵ as previously defined, or agroup convertible to R⁵, R^(4′) is a group R⁴ as previously defined, ora group convertible to R⁴, ring A is as previously defined, R′ is agroup R as previously defined, or a group convertible to R, Q is aspreviously defined, and Z is a leaving group such as chloro or bromo.Compounds of formula (XXXV) are commercially available, or can beprepared by reduction of the respective commercially availablenitrophenol.

It will be appreciated that compounds of formula (XXVI) can be pure cisor trans isomers, or a mixture of isomers. If necessary, separation ofpure cis and trans isomers after the reaction with (XXXV) can beachieved by chromatography or crystallisation.

Compounds of formula (X) can be prepared by a variety of processes e.g.as illustrated in Scheme 10 by

-   -   combining the alcohol/thiol (XIX) and the amine (XXV) with        phosgene or a phosgene equivalent using standard conditions.        Phosgene equivalents include carbonyl diimidazole, diphosgene,        triphosgene, phenyl chloroformate;        or    -   reacting the alcohol/thiol (XIX) with the isocyanate (XXXVII)        wherein R^(6′) is a group R⁶ as previously defined, or a group        convertible to R⁶, R^(5′) is a group R⁵ as previously defined,        or a group convertible to R⁵, R^(4′) is a group R⁴ as previously        defined, or a group convertible to R⁴, ring A is as previously        defined, R′ is a group R as previously defined, or a group        convertible to R, Y is O or S, Z is a leaving group such as        bromo, iodo, chloro or triflate, and Q is as previously defined.

The isocyanate (XXXVII) can be prepared from the corresponding amine(XXV) using standard methodology for isocyanate formation.

It will be appreciated that separation of the cis and trans isomers canbe achieved at any suitable stage in the synthesis.

Palladium and copper catalysts (XII) are commercially available or canbe prepared as described in the literature (see references in ProcessF).

Compounds of formula (XIII) are commercially available or can beprepared by literature processes.

Compounds of formula (XIV) where Q=H can be prepared as shown in Scheme11, by reductive alkylation of (XXXVIII) where Z′ represents Z or agroup convertible to Z with the ketone (III), and R′ is as previouslydefined. Compounds of formula (XXXVIII) in which Z′ is OH can beprepared by reduction of an N-protected piperidone, followed bydeprotection. Conversion of a Z′ hydroxy group to Z=chloro or bromo canbe accomplished using standard methodology e.g. treatment with thionylchloride or triphenylphosphine/carbon tetrabromide. It will beappreciated that separation of the cis and trans isomers can be achievedat any suitable stage in the synthesis.

The compound (XXV) where Q=H can be prepared as shown in Scheme 12.Reductive alkylation of the commercially available amine (XXXIX) withthe cyclohexanone (III) using for example sodium triacetoxyborohydridein dichloroethane provides the intermediate (XL) which is deprotectedusing HCl in ethanol or trifluoroacetic acid to afford the primary amine(XXV). It will be appreciated that separation of the cis and transisomers can be achieved at any suitable stage in the synthesis.

The compound (XXV) where Q=alkyl can be prepared from intermediates(XXXIX) and (III) using similar methodology as in process A2, followedby deprotection.

Alternatively the compounds (XXV) and (XXVI) where Q=H can be preparedas shown in Scheme 13. Reductive amination of cyclohexanone (III) usingfor example ammonia solution under catalytic hydrogenation conditionsprovides intermediate amine (XLI), which can be converted intopiperidinone (XXVI) by reaction with quaternary piperidine salt (XLII).Reductive amination, for example using ammonia and catalytichydrogenation, affords primary amine (XXV). It will be appreciated thatseparation of the cis and trans isomers can be achieved at any suitablestage in the synthesis.

Selective preparation of the cis and trans isomers of compound (XXV)where Q=H can be carried out via the process which is illustrated inScheme 14 for the trans isomer. The commercially available amine (XLIII)is initially N-protected, for example by incorporation in a phthalimidering, to give (XLIV), then the hydroxyl function converted into a silylprotected group, for example tert-butyldimethylsilyl, to give (XLV),which upon treatment with the appropriate aldehyde or ketone in thepresence of triethylsilane and bismuth tribromide affords (XLVI), whichafter deprotection gives intermediate amine (XLI). Conversion of amine(XLI) to the piperidinone (XXVI) by reaction with the quaternarypiperidine salt (XLII), followed by reductive amination, for exampleusing ammonia and catalytic hydrogenation, affords primary amine (XXV).

The cis isomer of compound (XXV) can be prepared by a similar procedurefrom the appropriate cis isomer of the amine (XLIII).

A selective preparation of the trans isomer of compounds (XXV) and(XXVI) where Q=Me is shown in Scheme 15. A suitable ester of4-hydroxycyclohexane carboxylic acid such as the methyl or ethyl ester(XLVII) wherein R″ is methyl or ethyl is protected as a silyl ether, forexample the tert-butyldimethylsilyl ether, to give (XLVIII), which ontreatment with the appropriate aldehyde or ketone in the presence oftriethylsilane and bismuth tribromide affords ether (XLIX). Hydrolysisto acid (L) followed by alkylation using a base such as lithiumdiisopropylamide with iodomethane affords mixture of cis and trans1-methylcyclohexane carboxylic acid (LI). The trans isomer (LII) can beisolated by conversion of the mixture to the acid chloride, for examplewith thionyl chloride, followed by selective hydrolysis of the productsby treatment with weak aqueous base such as sodium hydrogen carbonatesolution. The trans acid (LII) can be converted to the isocyanate (LIII)by Curtius rearrangement at elevated temperature of an intermediateazide prepared using for example diphenylphosphoryl azide, then theisocyanate hydrolysed to amine (LIV) under acidic conditions. Conversionof amine (LIV) to the piperidinone (XXVI) by reaction with quaternarypiperidine salt (XLII) followed by reductive amination, for exampleusing ammonia and catalytic hydrogenation, affords primary amine (XXV).Compounds of formula (XLVII) are commercially available.

An alternative preparation of the cis/trans acids (LI) is shown inScheme 16.

Diels-Alder reaction of 2-(trimethylsilyloxy)buta-1,3-diene with asuitable ester of methacrylic acid (e.g. R″=iso-butyl) affords, afterhydrolysis, the cyclohexanone (LVIII). Reductive alkylation using theappropriate alkoxy t-butyl dimethylsilane (R′OTBDMS), anhydrous ferricchloride and triethylsilane (see Iwanami et al, Synthesis 2005, 2669.).generates the ether (LIX) as a mixture of cis/trans isomers. Standardester hydrolysis using for example aqueous sodium hydroxide leads to theformation of the acids (LI) as a cis/trans mixture. Further syntheticelaboration is as detailed in Scheme 15.

The cis isomer of (XXV) where Q=Me can be obtained as shown in Scheme17. The mixture of acids (LI) is converted to a mixture of isocyanates(LV) via Curtius rearrangement of an intermediate azide at elevatedtemperature prepared using for example diphenylphosphoryl azide. The cisisomer (LVI) can be isolated from this mixture by chromatographicseparation, then converted through to amine (XXV) using a similarprocedure to that as shown for the trans isomer in Scheme 15 throughintermediates (LVII) and (XXVI).

Compounds of the present invention are M₁ receptor agonists. SelectiveM₁ receptor agonists are said to be useful to ameliorate positive andcognitive symptoms of psychotic disorders such as schizophrenia,schizo-affective disorders, schizophreniform diseases, psychoticdepression, mania, acute mania, paranoid and delusional disorders, andcognitive impairment including memory disorders such as Alzheimer'sdisease without peripheral cholinergic side effects mediatedpredominantly through M₂ and M₃ receptors. M₁ receptor agonists may alsobe suitable for combination with other typical and atypicalantipsychotics and other actives such as mood stabilisers,antidepressants, anxiolytics, drugs for extrapyramidal side effects andcognitive enhancers, to provide improved treatment of psychoticdisorders.

M₁ receptor agonists may also be suitable for treatment of theunderlying pathology associated with Alzheimer's Disease, or in apreventative role.

Thus in a further aspect, the invention provides a compound of formula(I) as hereinbefore described or a pharmaceutically acceptable saltthereof for use in therapy.

In another aspect, the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment of acondition wherein agonism of a muscarinic M₁ receptor would bebeneficial.

The terms describing the indications used herein are classified in theDiagnostic and Statistical Manual of Mental Disorders, 4th Edition,published by the American Psychiatric Association (DSM-IV) and/or theInternational Classification of Diseases, 10th Edition (ICD-10).Treatment of the various subtypes of the disorders mentioned herein iscontemplated as part of the present invention. Numbers in brackets afterthe listed diseases below refer to the classification code in DSM-IV.

Within the context of the present invention, the term psychotic disorderincludes Schizophrenia including the subtypes Paranoid Type (295.30),Disorganised Type (295.10), Catatonic Type (295.20), UndifferentiatedType (295.90) and Residual Type (295.60); Schizophreniform Disorder(295.40); Schizoaffective Disorder (295.70) including the subtypesBipolar Type and Depressive Type; Delusional Disorder (297.1) includingthe subtypes Erotomanic Type, Grandiose Type, Jealous Type, PersecutoryType, Somatic Type, Mixed Type and Unspecified Type; Brief PsychoticDisorder (298.8); Shared Psychotic Disorder (297.3); Psychotic DisorderDue to a General Medical Condition including the subtypes With Delusionsand With Hallucinations; Substance-Induced Psychotic Disorder includingthe subtypes With Delusions (293.81) and With Hallucinations (293.82);and Psychotic Disorder Not Otherwise Specified (298.9);

Other conditions wherein agonism of the M₁ receptor would be beneficialin their treatment include:

Depression and mood disorders including Major Depressive Episode, ManicEpisode, Mixed Episode and Hypomanic Episode; Depressive Disordersincluding Major Depressive Disorder, Dysthymic Disorder (300.4),Depressive Disorder Not Otherwise Specified (311); Bipolar Disordersincluding Bipolar I Disorder, Bipolar II Disorder (Recurrent MajorDepressive Episodes with Hypomanic Episodes) (296.89), CyclothymicDisorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80);Other Mood Disorders including Mood Disorder Due to a General MedicalCondition (293.83) which includes the subtypes With Depressive Features,With Major Depressive-like Episode, With Manic Features and With MixedFeatures), Substance-Induced Mood Disorder (including the subtypes WithDepressive Features, With Manic Features and With Mixed Features) andMood Disorder Not Otherwise Specified (296.90);

Anxiety disorders including Social Anxiety Disorder, Panic Attack,Agoraphobia, Panic Disorder, Agoraphobia Without History of PanicDisorder (300.22), Specific Phobia (300.29) including the subtypesAnimal Type, Natural Environment Type, Blood-Injection-Injury Type,Situational Type and Other Type), Social Phobia (300.23),Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder(309.81), Acute Stress Disorder (308.3), Generalized Anxiety Disorder(300.02), Anxiety Disorder Due to a General Medical Condition (293.84),Substance-Induced Anxiety Disorder and Anxiety Disorder Not OtherwiseSpecified (300.00);

Substance-related disorders including Substance Use Disorders such asSubstance Dependence, Substance Craving and Substance Abuse;Substance-Induced Disorders such as Substance Intoxication, SubstanceWithdrawal, Substance-Induced Delirium,

Substance-Induced Persisting Dementia, Substance-Induced PersistingAmnestic Disorder, Substance-Induced Psychotic Disorder,Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder,Substance-Induced Sexual Dysfunction, Substance-Induced Sleep Disorderand Hallucinogen Persisting Perception Disorder (Flashbacks);Alcohol-Related Disorders such as Alcohol Dependence (303.90), AlcoholAbuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal(291.81), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium,Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting AmnesticDisorder, Alcohol-Induced Psychotic Disorder, Alcohol-Induced MoodDisorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced SexualDysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related DisorderNot Otherwise Specified (291.9); Amphetamine (orAmphetamine-Like)-Related Disorders such as Amphetamine Dependence(304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89),Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium,Amphetamine Induced Psychotic Disorder, Amphetamine-Induced MoodDisorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-InducedSexual Dysfunction, Amphetamine-Induced Sleep Disorder andAmphetamine-Related Disorder Not Otherwise Specified (292.9); CaffeineRelated Disorders such as Caffeine Intoxication (305.90),Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder andCaffeine-Related Disorder Not Otherwise Specified (292.9);Cannabis-Related Disorders such as Cannabis Dependence (304.30),Cannabis Abuse (305.20), Cannabis Intoxication (292.89), CannabisIntoxication Delirium, Cannabis-Induced Psychotic Disorder,Cannabis-Induced Anxiety Disorder and Cannabis-Related Disorder NotOtherwise Specified (292.9); Cocaine-Related Disorders such as CocaineDependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication(292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium,Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder,Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction,Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder NotOtherwise Specified (292.9); Hallucinogen-Related Disorders such asHallucinogen Dependence (304.50), Hallucinogen Abuse (305.30),Hallucinogen Intoxication (292.89), Hallucinogen Persisting PerceptionDisorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium,Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced MoodDisorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-RelatedDisorder Not Otherwise Specified (292.9); Inhalant-Related Disorderssuch as Inhalant Dependence (304.60), Inhalant Abuse (305.90), InhalantIntoxication (292.89), Inhalant Intoxication Delirium, Inhalant-InducedPersisting Dementia, Inhalant-Induced Psychotic Disorder,Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder andInhalant-Related Disorder Not Otherwise Specified (292.9);Nicotine-Related Disorders such as Nicotine Dependence (305.1), NicotineWithdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified(292.9); Opioid-Related Disorders such as Opioid Dependence (304.00),Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal(292.0), Opioid Intoxication Delirium, Opioid-Induced PsychoticDisorder, Opioid-Induced Mood Disorder, Opioid-Induced SexualDysfunction, Opioid-Induced Sleep Disorder and Opioid-Related DisorderNot Otherwise Specified (292.9); Phencyclidine (orPhencyclidine-Like)-Related Disorders such as Phencyclidine Dependence(304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication(292.89), Phencyclidine Intoxication Delirium, Phencyclidine-InducedPsychotic Disorder, Phencyclidine-Induced Mood Disorder,Phencyclidine-Induced Anxiety Disorder and Phencyclidine-RelatedDisorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, orAnxiolytic-Related Disorders such as Sedative, Hypnotic, or AnxiolyticDependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40),Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative,Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, orAnxiolytic Intoxication Delirium, Sedative, Hypnotic, or AnxiolyticWithdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-PersistingDementia, Sedative-, Hypnotic-, or Anxiolytic-Persisting AmnesticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced PsychoticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Mood Disorder,Sedative-, Hypnotic-, or Anxiolytic-Induced Anxiety Disorder Sedative-,Hypnotic-, or Anxiolytic-Induced Sexual Dysfunction, Sedative-,Hypnotic-, or Anxiolytic-Induced Sleep Disorder and Sedative-,Hypnotic-, or

Anxiolytic-Related Disorder Not Otherwise Specified (292.9);Polysubstance-Related Disorder such as Polysubstance Dependence(304.80); and Other (or Unknown) Substance-Related Disorders such asAnabolic Steroids, Nitrate Inhalants and Nitrous Oxide;

Sleep disorders including primary sleep disorders such as Dyssomniassuch as Primary Insomnia (307.42), Primary Hypersomnia (307.44),Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), CircadianRhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified(307.47); primary sleep disorders such as Parasomnias such as NightmareDisorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder(307.46) and Parasomnia Not Otherwise Specified (307.47); SleepDisorders Related to Another Mental Disorder such as Insomnia Related toAnother Mental Disorder (307.42) and Hypersomnia Related to AnotherMental Disorder (307.44); Sleep Disorder Due to a General MedicalCondition; and Substance-Induced Sleep Disorder including the subtypesInsomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type;

Eating disorders such as Anorexia Nervosa (307.1) including the subtypesRestricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51)including the subtypes Purging Type and Nonpurging Type; Obesity;Compulsive Eating Disorder; and Eating Disorder Not Otherwise Specified(307.50);

Autistic Disorder (299.00); Attention-Deficit/Hyperactivity Disorderincluding the subtypes Attention-Deficit/Hyperactivity Disorder CombinedType (314.01), Attention-Deficit/Hyperactivity Disorder PredominantlyInattentive Type (314.00), Attention-Deficit/Hyperactivity DisorderHyperactive-Impulse Type (314.01) and Attention-Deficit/HyperactivityDisorder Not Otherwise Specified (314.9); Hyperkinetic Disorder;Disruptive Behaviour Disorders such as Conduct Disorder including thesubtypes childhood-onset type (321.81), Adolescent-Onset Type (312.82)and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81)and Disruptive Behaviour Disorder Not Otherwise Specified; and TicDisorders such as Tourette's Disorder (307.23);

Personality Disorders including the subtypes Paranoid PersonalityDisorder (301.0), Schizoid Personality Disorder (301.20), SchizotypalPersonality Disorder (301,22), Antisocial Personality Disorder (301.7),Borderline Personality Disorder (301,83), Histrionic PersonalityDisorder (301.50), Narcissistic Personality Disorder (301,81), AvoidantPersonality Disorder (301.82), Dependent Personality Disorder (301.6),Obsessive-Compulsive Personality Disorder (301.4) and PersonalityDisorder Not Otherwise Specified (301.9);

Sexual dysfunctions including Sexual Desire Disorders such as HypoactiveSexual Desire Disorder (302.71), and Sexual Aversion Disorder (302.79);sexual arousal disorders such as Female Sexual Arousal Disorder (302.72)and Male Erectile Disorder (302.72); orgasmic disorders such as FemaleOrgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) andPremature Ejaculation (302.75); sexual pain disorder such as Dyspareunia(302.76) and Vaginismus (306.51); Sexual Dysfunction Not OtherwiseSpecified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism(302.81), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism(302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3),Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9);gender identity disorders such as Gender Identity Disorder in Children(302.6) and Gender Identity Disorder in Adolescents or Adults (302.85);and Sexual Disorder Not Otherwise Specified (302.9); and

Alzheimer's Type Dementia including Dementia of the Alzheimer's Type,With Early Onset, Without Behavioural Disturbance (294.10); Dementia ofthe Alzheimer's Type, With Late Onset, Without Behavioural Disturbance(294.10); Dementia of the Alzheimer's Type, With Early Onset, WithBehavioural Disturbance (294.11); Dementia of the Alzheimer's Type, WithLate Onset, With Behavioural Disturbance (294.11).

The compounds of formula (I) may also be useful for the enhancement ofcognition, including both the treatment of cognitive impairment on itsown and the treatment of cognition impairment in other diseases such asschizophrenia, bipolar disorder, depression, other psychiatric disordersand psychotic conditions associated with cognitive impairment. Wherecognitive impairment results from a treatment of a disease, M₁ agonistsmay be beneficial. For example, when the treatment of epilepsy withanticonvulsants results in cognitive impairment, an M₁ agonist may beuseful for the alleviation or treatment of the cognitive impairment.

Within the context of the present invention, the term cognitiveimpairment includes, for example, impairment of cognitive functionsincluding attention, orientation, learning disorders, memory (i.e.memory disorders, amnesia, amnesic disorders, transient global amnesiasyndrome and age-associated memory impairment) and language function;cognitive impairment as a result of stroke, Alzheimer's disease,Huntington's disease, Pick disease, Aids-related dementia or otherdementia states such as Multiinfarct dementia, alcoholic dementia,hypotiroidism-related dementia, and dementia associated to otherdegenerative disorders such as cerebellar atrophy and amyotropic lateralsclerosis; other acute or sub-acute conditions that may cause cognitivedecline such as delirium or depression (pseudodementia states) trauma,head trauma, age related cognitive decline, stroke, neurodegeneration,drug-induced states, neurotoxic agents, mild cognitive impairment, agerelated cognitive impairment, autism related cognitive impairment,Down's syndrome, cognitive deficit related to psychosis, andpost-electroconvulsive treatment related cognitive disorders; anddyskinetic disorders such as Parkinson's disease, neuroleptic-inducedparkinsonism, and tardive dyskinesias.

Compounds of formula (I) or pharmaceutically accepatble salts thereofmay also be used as memory and/or cognition enhancers in healthy humanswith no cognitive and/or memory deficit.

In another aspect, the invention provides a compound of formula (I) ashereinbefore described or a pharmaceutically acceptable salt thereof foruse in the treatment of a psychotic disorder. In one embodiment, theinvention provides a compound of formula (I) as hereinbefore describedor a pharmaceutically acceptable salt thereof for use in the treatmentof schizophrenia.

The invention also provides a compound of formula (I) as hereinbeforedescribed or a pharmaceutically acceptable salt thereof for use in thetreatment of cognitive impairment.

The invention also provides a compound of formula (I) as hereinbeforedescribed or a pharmaceutically acceptable salt thereof for use in thetreatment of Alzheimer's Disease.

In another aspect, the invention provides the use of a compound offormula (I) as hereinbefore described or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for the treatment of acondition wherein agonism of the M₁ receptor would be beneficial.

In another aspect, the invention provides the use of a compound offormula (I) as hereinbefore described or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for the treatment of apsychotic disorder. In one embodiment, the invention provides the use ofa compound of formula (I) as hereinbefore described or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of schizophrenia.

In another aspect, the invention provides a compound of formula (I) ashereinbefore described or a pharmaceutically acceptable salt thereof forthe treatment of a psychotic disorder. In one embodiment, the inventionprovides a compound of formula (I) as hereinbefore described or apharmaceutically acceptable salt thereof for the treatment ofschizophrenia.

The invention also provides the use of a compound of formula (I) ashereinbefore described or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament for the treatment of cognitiveimpairment.

The invention also provides a compound of formula (I) as hereinbeforedescribed or a pharmaceutically acceptable salt thereof for thetreatment of cognitive impairment.

The invention also provides the use of a compound of formula (I) ashereinbefore described or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament for the treatment of Alzheimer'sDisease.

The invention also provides a compound of formula (I) as hereinbeforedescribed or a pharmaceutically acceptable salt thereof for thetreatment of Alzheimer's Disease.

In another aspect, the invention provides a method of treating acondition where agonism of the M₁ receptor would be beneficial, whichcomprises administering to a mammal in need thereof an effective amountof a compound of formula (I) as hereinbefore described or apharmaceutically acceptable salt thereof. In one embodiment, the mammalis a human.

In another aspect, the invention provides a method of treating apsychotic disorder which comprises administering to a mammal in needthereof an effective amount of a compound of formula (I) as hereinbeforedescribed or a pharmaceutically acceptable salt thereof. In oneembodiment, the invention provides a method of treating schizophrenia,which comprises administering to a mammal in need thereof an effectiveamount of a compound of formula (I) as hereinbefore described or apharmaceutically acceptable salt thereof. In one embodiment, the mammalis a human.

The invention also provides a method of treating cognitive impairment,which comprises administering to a mammal in need thereof an effectiveamount of a compound of formula (I) as hereinbefore described or apharmaceutically acceptable salt thereof. In one embodiment, the mammalis a human.

The invention also provides a method of treating Alzheimer's Disease,which comprises administering to a mammal in need thereof an effectiveamount of a compound of formula (I) as hereinbefore described or apharmaceutically acceptable salt thereof. In one embodiment, the mammalis a human.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be suitable for combination with other actives, such astypical and atypical antipsychotics, mood stabilisers, antidepressants,anxiolytics, drugs for extrapyrimidal side effects and cognitiveenhancers to provide improved treatment of psychotic disorders.

The combination therapies of the invention are, for example,administered adjunctively. By adjunctive administration is meant thecoterminous or overlapping administration of each of the components inthe form of separate pharmaceutical compositions or devices. This regimeof therapeutic administration of two or more therapeutic agents isreferred to generally by those skilled in the art and herein asadjunctive therapeutic administration; it is also known as add-ontherapeutic administration. Any and all treatment regimes in which apatient receives separate but coterminous or overlapping therapeuticadministration of the compounds of formula (I) or a pharmaceuticallyacceptable salt thereof and at least one antipsychotic agent, a moodstabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidalside effects or a cognitive enhancer are within the scope of the currentinvention. In one embodiment of adjunctive therapeutic administration asdescribed herein, a patient is typically stabilised on a therapeuticadministration of one or more of the components for a period of time andthen receives administration of another component. The compounds offormula (I) or a pharmaceutically acceptable salt thereof may beadministered as adjunctive therapeutic treatment to patients who arereceiving administration of at least one antipsychotic agent, a moodstabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidalside effects or a cognitive enhancer, but the scope of the inventionalso includes the adjunctive therapeutic administration of at least oneantipsychotic agent, a mood stabiliser, an antidepressant, ananxiolytic, a drug for extrapyrimidal side effects or a cognitiveenhancer to patients who are receiving administration of compounds offormula (I) or a pharmaceutically acceptable salt thereof.

The combination therapies of the invention may also be administeredsimultaneously. By simultaneous administration is meant a treatmentregime wherein the individual components are administered together,either in the form of a single pharmaceutical composition or devicecomprising or containing both components, or as separate compositions ordevices, each comprising one of the components, administeredsimultaneously. Such combinations of the separate individual componentsfor simultaneous combination may be provided in the form of akit-of-parts.

In a further aspect therefore, the invention provides a method oftreatment of a psychotic disorder by adjunctive therapeuticadministration of compounds of formula (I) or a pharmaceuticallyacceptable salt thereof to a patient receiving therapeuticadministration of at least one antipsychotic agent. In a further aspect,the invention provides the use of compounds of formula (I) or apharmaceutically acceptable salt thereof in the manufacture of amedicament for adjunctive therapeutic administration for the treatmentof a psychotic disorder in a patient receiving therapeuticadministration of at least one antipsychotic agent. In a further aspect,the invention provides compounds of formula (I) or a pharmaceuticallyacceptable salt thereof for adjunctive therapeutic administration forthe treatment of a psychotic disorder in a patient receiving therapeuticadministration of at least one antipsychotic agent. The inventionfurther provides compounds of formula (I) or a pharmaceuticallyacceptable salt thereof for use for adjunctive therapeuticadministration for the treatment of a psychotic disorder in a patientreceiving therapeutic administration of at least one antipsychoticagent.

In a further aspect, the invention provides a method of treatment of apsychotic disorder by adjunctive therapeutic administration of at leastone antipsychotic agent to a patient receiving therapeuticadministration of compounds of formula (I) or a pharmaceuticallyacceptable salt thereof. In a further aspect, the invention provides theuse of at least one antipsychotic agent in the manufacture of amedicament for adjunctive therapeutic administration for the treatmentof a psychotic disorder in a patient receiving therapeuticadministration of compounds of formula (I) or a pharmaceuticallyacceptable salt thereof. In a further aspect, the invention provides atleast one antipsychotic agent for adjunctive therapeutic administrationfor the treatment of a psychotic disorder in a pateient recievingtherapeutic administration of compounds of formula (I) or apharmaceutically acceptable salt thereof. The invention further providesat least one antipsychotic agent for adjunctive therapeuticadministration for the treatment of a psychotic disorder in a patientreceiving therapeutic administration of compounds of formula (I) or apharmaceutically acceptable salt thereof.

In a further aspect, the invention provides a method of treatment of apsychotic disorder by simultaneous therapeutic administration ofcompounds of formula (I) or a pharmaceutically acceptable salt thereofin combination with at least one antipsychotic agent. The inventionfurther provides the use of a combination of compounds of formula (I) ora pharmaceutically acceptable salt thereof and at least oneantipsychotic agent in the manufacture of a medicament for simultaneoustherapeutic administration in the treatment of a psychotic disorder. Theinvention further provides a combination of compounds of formula (I) ora pharmaceutically acceptable salt thereof and at least one antipsycoticagent for simultaneous therapeutic administration in the treatment of apsychotic disorder. The invention further provides the use of compoundsof formula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for simultaneous therapeutic administrationwith at least one antipsychotic agent in the treatment of a psychoticdisorder. The invention further provides compounds of formula (I) or apharmaceutically acceptable salt thereof for use for simultaneoustherapeutic administration with at least one antipsychotic agent in thetreatment of a psychotic disorder. The invention further provides theuse of at least one antipsychotic agent in the manufacture of amedicament for simultaneous therapeutic administration with compounds offormula (I) or a pharmaceutically acceptable salt thereof in thetreatment of a psychotic disorder. The invention further provides atleast one antipsychotic agent for simultaneous therapeuticadministration with compounds of formula (I) or a pharmaceuticallyacceptable salt thereof in the treatment of a psychotic disorder.

In a further aspect, the invention provides a kit-of-parts for use inthe treatment of a psychotic disorder comprising a first dosage formcomprising compounds of formula (I) or a pharmaceutically acceptablesalt thereof and one or more further dosage forms each comprising anantipsychotic agent for simultaneous therapeutic administration.

In another aspect, the invention provides a method of treatment of apsychotic disorder by adjunctive therapeutic administration of acompound of the present invention to a patient receiving therapeuticadministration of an active ingredient selected from the groupconsisting of: a mood stabiliser, an antidepressant, an anxiolytic, adrug for extrapyrimidal side effects and a cognitive enhancer.

In a further aspect, the invention provides the use of a compound of thepresent invention in the manufacture of a medicament for adjunctivetherapeutic administration for the treatment of a psychotic disorder ina patient receiving therapeutic administration of an active ingredientselected from the group consisting of: a mood stabiliser, anantidepressant, an anxiolytic, a drug for extrapyrimidal side effectsand a cognitive enhancer.

The invention also provides a compound of the present invention foradjunctive therapeutic administration for the treatment of a psychoticdisorder in a patient receiving therapeutic administration of an activeingredient selected from the group consisting of: a mood stabiliser, anantidepressant, an anxiolytic, a drug for extrapyrimidal side effectsand a cognitive enhancer.

The invention also provides the use of a compound of the presentinvention in adjunctive therapeutic administration for the treatment ofa psychotic disorder in a patient receiving therapeutic administrationof an active ingredient selected from the group consisting of: a moodstabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidalside effects and a cognitive enhancer.

The invention further provides the use of a compound of the presentinvention for use for adjunctive therapeutic administration for thetreatment of a psychotic disorder in a patient receiving therapeuticadministration of an active ingredient selected from the groupconsisting of: a mood stabiliser, an antidepressant, an anxiolytic, adrug for extrapyrimidal side effects and a cognitive enhancer.

In a further aspect, the invention provides a method of treatment of apsychotic disorder by adjunctive therapeutic administration of an activeingredient selected from the group consisting of: a mood stabiliser, anantidepressant, an anxiolytic, a drug for extrapyrimidal side effectsand a cognitive enhancer to a patient receiving therapeuticadministration of a compound of the present invention.

In a further aspect, the invention provides the use of an activeingredient selected from the group consisting of: a mood stabiliser, anantidepressant, an anxiolytic, a drug for extrapyrimidal side effectsand a cognitive enhancer in the manufacture of a medicament foradjunctive therapeutic administration for the treatment of a psychoticdisorder in a patient receiving therapeutic administration of a compoundof the present invention.

The invention also provides an active ingredient selected from the groupconsisting of: a mood stabiliser, an antidepressant, an anxiolytic, adrug for extrapyrimidal side effects and a cognitive enhancer foradjunctive therapeutic administration for the treatment of a psychoticdisorder in a patient receiving therapeutic administration of a compoundof the present invention

The invention also provides the use of an active ingredient selectedfrom the group consisting of: a mood stabiliser, an antidepressant, ananxiolytic, a drug for extrapyrimidal side effects and a cognitiveenhancer for adjunctive therapeutic administration for the treatment ofa psychotic disorder in a patient receiving therapeutic administrationof a compound of the present invention

In a further aspect, the invention provides a method of treatment of apsychotic disorder by simultaneous therapeutic administration of acompound of the present invention in combination with an activeingredient selected from the group consisting of: a mood stabiliser, anantidepressant, an anxiolytic, a drug for extrapyrimidal side effectsand a cognitive enhancer.

The invention further provides the use of a combination of a compound ofthe present invention and an active ingredient selected from the groupconsisting of: a mood stabiliser, an antidepressant, an anxiolytic, adrug for extrapyrimidal side effects and a cognitive enhancer in themanufacture of a medicament for simultaneous therapeutic administrationin the treatment of a psychotic disorder.

The invention further provides a combination of a compound of thepresent invention and an active ingredient selected from the groupconsisting of: a mood stabiliser, an antidepressant, an anxiolytic, adrug for extrapyrimidal side effects and a cognitive enhancer forsimultaneous therapeutic administration for the treatment of a psychoticdisorder.

The invention further provides the use of a combination of a compound ofthe present invention and an active ingredient selected from the groupconsisting of: a mood stabiliser, an antidepressant, an anxiolytic, adrug for extrapyrimidal side effects and a cognitive enhancer forsimultaneous therapeutic administration in the treatment of a psychoticdisorder.

The invention further provides the use of a compound of the presentinvention in the manufacture of a medicament for simultaneoustherapeutic administration with an active ingredient selected from thegroup consisting of: a mood stabiliser, an antidepressant, ananxiolytic, a drug for extrapyrimidal side effects and a cognitiveenhancer in the treatment of a psychotic disorder.

The invention further provides a compound of the present invention forsimultaneous therapeutic administration with an active ingredientselected from the group consisting of: a mood stabiliser, anantidepressant, an anxiolytic, a drug for extrapyrimidal side effectsand a cognitive enhancer for the treatment of a psychotic disorder.

The invention further provides the use of a compound of the presentinvention for simultaneous therapeutic administration with an activeingredient selected from the group consisting of: a mood stabiliser, anantidepressant, an anxiolytic, a drug for extrapyrimidal side effectsand a cognitive enhancer in the treatment of a psychotic disorder.

The invention further provides a compound of the present invention foruse for simultaneous therapeutic administration with an activeingredient selected from the group consisting of: a mood stabiliser, anantidepressant, an anxiolytic, a drug for extrapyrimidal side effectsand a cognitive enhancer in the treatment of a psychotic disorder.

The invention further provides the use of an active ingredient selectedfrom the group consisting of: a mood stabiliser, an antidepressant, ananxiolytic, a drug for extrapyrimidal side effects and a cognitiveenhancer in the manufacture of a medicament for simultaneous therapeuticadministration with a compound of the present invention in the treatmentof a psychotic disorder.

The invention further provides an active ingredient selected from thegroup consisting of: a mood stabiliser, an antidepressant, ananxiolytic, a drug for extrapyrimidal side effects and a cognitiveenhancer for simultaneous therapeutic administration with a compound ofthe present invention for the treatment of a psychotic disorder.

The invention further provides the use of an active ingredient selectedfrom the group consisting of: a mood stabiliser, an antidepressant, ananxiolytic, a drug for extrapyrimidal side effects and a cognitiveenhancer for simultaneous therapeutic administration with a compound ofthe present invention in the treatment of a psychotic disorder.

In a further aspect, the invention provides a kit-of-parts for use inthe treatment of a psychotic disorder comprising a first dosage formcomprising a compound of the present invention and one or more furtherdosage forms each comprising an active ingredient selected from thegroup consisting of: a mood stabiliser, an antidepressant, ananxiolytic, a drug for extrapyrimidal side effects and a cognitiveenhancer for simultaneous therapeutic administration.

In one embodiment, the patient is a human.

Examples of antipsychotic drugs that may be useful in the presentinvention include, but are not limited to: sodium channel blockers;mixed 5HT/dopamine receptor antagonists; mGluR5 positive modulators; D3antagonists; 5HT6 angatonists; nicotinic alpha-7 modulators; glycinetransporter GlyT1 inhibitors; D2 partial agonist/D3 antanogist/H3antagonists; AMPA modulators; NK3 antagonists such as osanetant andtalnetant; an atypical antipsychotic, for example clozapine, olanzapine,risperidone, quetiapine, aripirazole, ziprasidone and amisulpride;butyrophenones, such as haloperidol, pimozide, and droperidol;phenothiazines, such as chlorpromazine, thioridazine, mesoridazine,trifluoperazine, perphenazine, fluphenazine, thiflupromazine,prochlorperazine, and acetophenazine; thioxanthenes, such as thiothixeneand chlorprothixene; thienobenzodiazepines; dibenzodiazepines;benzisoxazoles; dibenzothiazepines; imidazolidinones;benzisothiazolyl-piperazines; triazine such as lamotrigine;dibenzoxazepines, such as loxapine; dihydroindolones, such as molindone;aripiprazole; and derivatives thereof that have antipsychotic activity.

Examples of tradenames and suppliers of selected antipsychotic drugsthat may be suitable for use in the present invention are as follows:clozapine (available under the tradename CLOZARIL®, from Mylan, ZenithGoldline, UDL, Novartis); olanzapine (available under the tradenameZYPREXA®, from Lilly); ziprasidone (available under the tradenameGEODON®, from Pfizer); risperidone (available under the tradenameRISPERDAL®, from Janssen); quetiapine fumarate (available under thetradename SEROQUEL®, from AstraZeneca); sertindole (available under thetradename SERLECT®); amisulpride (available under the tradename SOLION®,from Sanofi-Synthelabo); haloperidol (available under the tradenameHALDOL®, from Ortho-McNeil); haloperidol decanoate (available under thetradename HALDOL Decanoate®); haloperidol lactate (available under thetradenames HALDOL® and INTENSOL®); chlorpromazine (available under thetradename THORAZINE®, from SmithKline Beecham (GSK)); fluphenazine(available under the tradename PROLIXIN®, from Apothecon, Copley,Schering, Teva, and American Pharmaceutical Partners, Pasadena);fluphenazine decanoate (available under the tradename PROLIXINdecanoate®); fluphenazine enanthate (available under the tradenamePROLIXIN®); fluphenazine hydrochloride (available under the tradenamePROLIXIN®); thiothixene (available under the tradename NAVANE®, fromPfizer); thiothixene hydrochloride (available under the tradenameNAVANE®); trifluoperazine(10-[3-(4-methyl-1-piperazinyl)propyl]-2-(trifluoromethyl)phenothiazinedihydrochloride, available under the tradename STELAZINE®, fromSmithKline Beckman); perphenazine (available under the tradenameTRILAFON®, from Schering); perphenazine and amitriptyline hydrochloride(available under the tradename ETRAFON TRILAFON®); thioridazine(available under the tradename MELLARIL®; from Novartis, Roxane, HiTech,Teva, and Alpharma); molindone (available under the tradename MOBAN®,from Endo); molindone hydrochloride (available under the tradenameMOBAN®); loxapine (available under the tradename LOXITANE®; fromWatson); loxapine hydrochloride (available under the tradenameLOXITANE®); and loxapine succinate (available under the tradenameLOXITANE®). Furthermore, benperidol (Glianimon®), perazine (Taxilan®) ormelperone (Eunerpan®)) may be used.

Other suitable antipsychotic drugs include promazine (available underthe tradename SPARINE®), triflurpromazine (available under the tradenameVESPRIN®), chlorprothixene (available under the tradename TARACTAN®),droperidol (available under the tradename INAPSINE®), acetophenazine(available under the tradename TINDAL®;), prochlorperazine (availableunder the tradename COMPAZINE®), methotrimeprazine (available under thetradename NOZINAN®), pipotiazine (available under the tradenamePIPOTRIL®), iloperidone, pimozide and flupenthixol.

The antipsychotic drugs listed above by Tradename may also be availablefrom other suppliers under a different Tradename.

In one further aspect of the invention, suitable antipsychotic agentsinclude olanzapine, risperidone, quetiapine, amisulpride, aripiprazole,haloperidol, clozapine, olanzepine, ziprasidone, talnetant andosanetant.

Mood stabilisers which may be used in the therapy of the presentinvention include lithium, sodium valproate/valproic acid/divalproex,carbamazepine, lamotrigine, gabapentin, topiramate, oxcarbazepine andtiagabine.

Antidepressant drugs which may be used in the therapy of the presentinvention include serotonin antagonists, CRF-1 antagonists, Cox-2inhibitor/SSRI dual antagonists; dopamine/noradrenaline/serotonin triplereuptake inhibitors; NK1 antagonists; NK1 and NK2 dual antagonists;NK1/SSRI dual antagonists; NK2 antagonists; serotonin agonists (such asrauwolscine, yohimbine and metoclopramide); serotonin reuptakeinhibitors (such as citalopram, escitalopram, fluoxetine, fluvoxamine,femoxetine, indalpine, zimeldine, paroxetine and sertraline); dualserotonin/noradrenaline reuptake inhibitors (such as venlafaxine,reboxetine, duloxetine and milnacipran); Noradrenaline reuptakeinhibitors (such as reboxetine); tricyclic antidepressants (such asamitriptyline, clomipramine, imipramine, maprotiline, nortriptyline andtrimipramine); monoamine oxidase inhibitors (such as isocarboxazide,moclobemide, phenelzine and tranylcypromine); 5HT3 antagonists (such asexample ondansetron and granisetron); and others (such as bupropion,amineptine, radafaxine, mianserin, mirtazapine, nefazodone andtrazodone).

Anxiolytics which may be used in the therapy of the present inventioninclude V1b antagonists, 5HT7 antagonists and benzodiazepines such asalprazolam and lorazepam.

Drugs for extrapyramidal side effects which may be used in the therapyof the present invention include anticholinergics (such as benztropine,biperiden, procyclidine and trihexyphenidyl), antihistamines (such asdiphenhydramine) and dopaminergics (such as amantadine).

Cognitive enhancers which may be used in the therapy of the presentinvention include example cholinesterase inhibitors (such as tacrine,donepezil, rivastigmine and galantamine), H3 antagonists and muscarinicM₁ agonists (such as cevimeline).

For use in medicine, the compounds of the present invention are usuallyadministered as a standard pharmaceutical composition. The presentinvention therefore provides in a further aspect a pharmaceuticalcomposition comprising a compound of formula (I) as hereinbeforedescribed or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier. The pharmaceutical composition canbe for use in the treatment of any of the conditions described herein.In a further aspect, the invention provides a process for preparing apharmaceutical composition, the process comprising mixing a compound offormula (I) as hereinbefore described or a pharmaceutically acceptablesalt thereof and one or more pharmaceutically acceptable carriers. In afurther aspect, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) as hereinbefore described or apharmaceutically acceptable salt thereof in combination with at least 1antipsychotic, and one or more pharmaceutically acceptable carriers. Ina further aspect, the invention provides a process for preparing apharmaceutical composition, the process comprising mixing a compound offormula (I) as hereinbefore described or a pharmaceutically acceptablesalt thereof, at least 1 antipsychotic, and one or more pharmaceuticallyacceptable carriers.

The compounds of the invention may be administered by any convenientmethod, for example by oral, parenteral (e.g. intravenous), buccal,sublingual, nasal, rectal or transdermal administration and thepharmaceutical compositions adapted accordingly.

The compounds of the invention which are active when given orally can beformulated as liquids or solids, for example syrups, suspensions oremulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound o the invention or salt in a suitable liquid carrier(s)for example an aqueous solvent such as water, ethanol or glycerine, or anon-aqueous solvent, such as polyethylene glycol or an oil. Theformulation may also contain a suspending agent, preservative,flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example, pellets containing the activeingredient can be prepared using standard carriers and then filled intoa hard gelatin capsule; alternatively, a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), for exampleaqueous gums, celluloses, silicates or oils and the dispersion orsuspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or salt in a sterile aqueous carrier or parenterallyacceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone,lecithin, arachis oil or sesame oil. Alternatively, the solution can belyophilised and then reconstituted with a suitable solvent just prior toadministration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active substance in apharmaceutically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal once the contents of the container have been exhausted. Wherethe dosage form comprises an aerosol dispenser, it will contain apropellant which can be a compressed gas such as compressed air or anorganic propellant such as a fluorochloro-hydrocarbon. The aerosoldosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration are conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter.

Compositions suitable for transdermal administration include ointments,gels and patches. The composition may be in unit dose form such as atablet, capsule or ampoule.

Each dosage unit for oral administration contains, for example, from 1to 250 mg (and for parenteral administration contains, for example, from0.1 to 25 mg) of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof calculated as the free base.

The daily dosage contains suitably from 0.01 mg/kg to 100 mg/kg of acompound of formula (I) or a pharmaceutically acceptable salt thereofcalculated as the free base.

It will be appreciated that the precise dose administered will depend onthe age and condition of the patient and the frequency and route ofadministration and will be at the ultimate discretion of the attendantphysician.

The antipsychotic agent component or components used in the adjunctivetherapy of the present invention may also be administered in their basicor acidic forms as appropriate or, where appropriate, in the form of apharmaceutically acceptable salt or other derivative. All solvates andall alternative physical forms of the antipsychotic agent or agents ortheir salts or derivatives as described herein, including but notlimited to alternative crystalline forms, amorphous forms andpolymorphs, are also within the scope of this invention. In the case ofthe antipsychotic agent or agents, the forms and derivatives are, forexample, those which are approved for therapeutic administration asmonotherapies, including those mentioned above, but all references toantipsychotic agents herein include all salts or other derivativesthereof, and all solvates and alternative physical forms thereof.

For adjunctive therapeutic administration according to the invention,compounds of formula (I) or pharmaceutically acceptable salts thereofand the antipsychotic agent or agents or their salts, derivatives orsolvates may each be administered in pure form, but each of thecomponents will, for example, be formulated into any suitablepharmaceutically acceptable and effective composition which provideseffective levels of the respective component in the body. The choice ofthe most appropriate pharmaceutical compositions for each component iswithin the skill of the art, and may be the same form or different formsfor each of the components. Suitable formulations include, but are notlimited to tablets, capsules, powders, granules, lozenges,suppositories, reconstitutable powders, or liquid preparations such asoral or sterile parenteral solutions or suspensions.

For simultaneous administration as a combined composition of compoundsof formula (I) and the antipsychotic agent or agents according to theinvention, compounds of formula (I) or their pharmaceutically acceptablesalts and the antipsychotic agent or agents and their salts, derivativesor solvates may be administered together in pure form, but the combinedcomponents will, for example, be formulated into any suitablepharmaceutically acceptable and effective composition which provideseffective levels of each of the components in the body. The choice ofthe most appropriate pharmaceutical compositions for the combinedcomponents is within the skill of the art. Suitable formulationsinclude, but are not limited to tablets, sub-lingual tablets, buccalcompositions, capsules, powders, granules, lozenges, suppositories,reconstitutable powders, or liquid preparations such as oral or sterileparenteral solutions or suspensions.

In order to obtain consistency of adjunctive administration, thecompositions of each of the components, or of the combination of thecomponents is, for example, in the form of a unit dose.

The term “treatment” includes prophylaxis, where this is appropriate forthe relevant condition(s).

Biological Test Methods FLIPR Experiments on M₁ Receptors to DetermineAgonist/Antagonist Potency

Compounds of the invention were characterized in a functional assay todetermine their ability to activate the intracellular calcium pathway inCHO cells with stable expression of human muscarinic M₁ receptors usingFLIPR (Fluorometric Imaging Plate Reader) technology. Briefly, CHO-M₁cells were plated (15,000/well) and allowed to grow overnight at 37degrees. Media were removed and 30 μL loading buffer (HBSS with 2.5 mMprobenicid, 2 μM Fluo-4, 500 μM Brilliant Black, pH 7.4) was added.After incubation at 37 degrees for 90 minutes, 10 μL of the assay buffer(HBSS with 2.5 mM probenecid, pH 7.4) containing test compounds wasadded to each well on the FLIPR instrument. Calcium response wasmonitored to determine agonism. Plates were then incubated for another30 minutes before 10 μL of assay buffer containing acetylcholine wasadded at an EC₈₀, as the agonist challenge. Calcium response was thenmonitored again to determine compound's antagonism to acetylcholine.Concentration-response curves of both agonism and antagonism on M₁receptors were performed for each compound. Results were imported intoActivityBase data analysis suite (ID Business Solution Inc., Parsippany,N.J.) where the curves were analysed by non-linear curve fitting and theresulting pEC₅₀/fpKi were calculated. The maximum asymptotes of agonistcompounds were calculated as percentage of maximum FLIPR responseinduced by carbamoylcholine chloride added as control on the samecompound plates.

The example compounds below were tested in the above assay and werefound to have average pEC₅₀ values of >5.5 at the muscarinic M₁receptor, and intrinsic activity >50%.

FLIPR Experiments on M₂₋₅ Receptor to Determine Receptor SubtypeSelectivity

To determine selectivity of compounds of the invention against othermuscarinic receptor subtypes, compounds were characterized in FLIPRexperiments in CHO cells with stable expression of human muscarinicreceptors, M₂, M₃, M₄ or M₅. In the case of M₂ and M₄ receptors,chimeric G-protein Gqi5 was also co-expressed to couple receptors to thecalcium signalling pathway. Briefly, cells were plated (15,000/well) andallowed to grow overnight at 37 degrees. The FLIPR experiment was thencarried out on the next day using the same protocol as described abovefor CHO-M1 cells. Results were imported into ActivityBase data analysissuite where the curves were analysed by non-linear curve fitting and theresulting pEC₅₀/fpKi values were calculated.

The example compounds below were tested in the M₂₋₅ receptor assays andthe majority of the examples were found to be selective for the M₁receptor over M₂, M₃, M₄ and M₅ receptors, with typical selectivity(ratio of pEC₅₀'s) of ≧10-fold, and in certain cases ≧100-fold.

FLIPR Experiments on M₁ Receptor to Determine Agonist Intrinsic Activity

To determine the intrinsic activities of M₁ agonist compounds, compoundsof the invention were characterized in FLIPR experiments on CHO-K1 cellswith transient expression of human muscarinic M₁ receptors. Briefly,CHO-K1 cells were transduced with M₁ BacMam virus (Ames, R S; Formwald,J A; Nuthulaganti, P; Trill, J J; Foley, J J; Buckley, P T; Kost, T A;Wu, Z and Romanos, M A. (2004) Use of BacMam recombinant baculovirusesto support G protein-coupled receptor drug discovery. Receptors andChannels 10 (3-4): 99-109). A functional titration was performed on eachbatch of cells continuously cultured ahead of experimentation todetermine the appropriate multiplicity of infection ratio (MOI) formeasuring intrinsic activities of test compounds. After mixing withvirus in suspension, cells were plated (10,000/well) and allowed toadhere overnight at 37 degrees.

The FLIPR experiment was carried out on the day following plating usingthe same protocol as described above for CHO-M₁ cells. Data was analysedby non-linear curve fitting using four-parameter logistics contained inXC50 version 2, and the resulting pEC₅₀ values were calculated. Theintrinsic activities of agonist compounds were measured as percentage ofmaximum FLIPR response induced by acetylcholine added as control on thesame compound plates, and converted to a fraction between 0 and 1 (i.e.calculated using a 100% max response from a fitted acetylcholinestandard curve, containing multiple concentrations, as control).

Certain compounds below were tested in this assay, and were found tohave average pEC₅₀ values of >6.0 at the muscarinic M₁ receptor, andintrinsic activity of greater than or equal to 0.3.

The invention is further illustrated by the following non-limitingexamples. In the procedures that follow, after each starting material,reference to a Description by number is typically provided. This isprovided merely for assistance to the skilled chemist. The startingmaterial may not necessarily have been prepared from the batch referredto.

SCX columns (including SCX, SCX-2, SCX-3) refer to sulfonic acid ionexchange resins supplied by Varian, IST and Radleys.

Amino-doped Silica Columns are Supplied by Biotage

SPE-Si cartridges are silica solid phase extraction columns supplied byVarian.

Flash silica gel chromatography was carried out on, for example, silicagel 230-400 mesh (supplied by Merck AG Darmstadt, Germany) or overpre-packed Biotage silica cartridges (e.g. 12+M, or 65i) on BiotageHorizon, SP1 or SP4 machines.

For specified hydrogenation reactions, an H-cube was used. The H-cube isa continuous flow hydrogenator developed by Thales Nanotechnology. Asolution of the sample to be hydrogenated is delivered to the reactor ina continuous stream using an HPLC pump. In the reactor it is mixed withhydrogen (generated from electrolysis of water), heated, and passedthrough a catalyst (e.g. palladium on charcoal) cartridge (up to 100° C.and 100 bar pressure) to produce a continuous flow of hydrogenatedproduct.

NMR spectra were obtained at 298° K, at the frequency stated usingeither a Bruker™ DPX400 or an Oxford Instruments™ 250 MHz machine andrun as a dilute solution of CDCl₃ unless otherwise stated. All NMRspectra were reference to tetramethylsilane (TMS δ_(H) 0, δ_(C) 0). Allcoupling constants are reported in hertz (Hz), and multiplicities arelabelled (singlet), bs, (broad singlet), d (doublet), t (triplet), q(quartet), dd (doublet of doublets), dt (doublet of triplets) and m(multiplet). NMR spectral data, where provided, were obtained for thetitle substance in each Description or Example (e.g. the hydrochloridesalt, or the free base), unless otherwise stated.

Mass spectra (MS) were taken on a 4 II triple quadropole MassSpectrometer (Micromass UK) or on a Agilent MSD 1100 Mass Spectrometer,operating in ES (+) and ES (−) ionization mode or on a Agilent LC/MSD1100 Mass Spectrometer, operating in ES (+) and ES (−) ionization modecoupled with HPLC instrument Agilent 1100 Series [LC/MS-ES (+)].Analysis was performed on a Waters Atlantis column (50×4.6 mm) with astationary phase particle size of 3 μM. Mobile phase A (aqueousphase)=water+0.05% formic acid; mobile phase B (organicsolvent)=acetonitrile+0.05% formic acid. Method as follows:

Time/min % A % B 0 97 3 0.1 97 3 4 3 97 4.8 3 97 4.9 97 3 5.0 97 3

The above method had a flow rate of 3 mL/min. The injection volume was 5μL. The column temperature was 30° C. The UV detection range was from220 to 330 nm.

MDAP (mass-directed auto-preparation) refers to purification by HPLC ona Waters machine, wherein fraction collection is triggered by detectionof the programmed mass ion for the compound of interest. High pHseparations refer to use of a water/acetonitrile/ammonium carbonategradient.

MDAP was conducted using a Waters 2525 Binary Gradient Module, a Waters515 Makeup Pump, a Waters Pump Control Module, a Waters 2767 InjectCollect, a Waters Column Fluidics Manager, a Waters 2996 PhotodiodeArray Detector, a Waters ZQ Mass Spectrometer, a Gilson 202 fractioncollector and a Gilson Aspec waste collector. For low pH, the column wasa Waters Atlantis or Sunfire C18 column (19×100 mmm or 30×100 mm, 5 μmpacking diameter), solvent A was water plus 0.1% formic acid and solventB was acetonitrile plus 0.1% formic acid. The gradient used wasdetermined by LCMS retention time.

LCMS Rt Gradient 1.0-1.5  5-30% B 1.5-2.2 15-55% B 2.2-2.9 30-85% B2.9-3.6 50-99% B 3.6-5.0 80-99% B

For high pH, the column was an X Bridge C18 column (30×100 mm, 5 μmpacking diameter), solvent A was 10 mM ammonium carbonate in wateradjusted to pH 10 using ammonia solution and solvent B was acetonitrile.The gradient was determined by LCMS retention time:

LCMS Rt Gradient 1.0-1.5  1-99% B 1.5-2.2 15-99% B 2.2-2.9 30-99% B2.9-3.6 50-99% B 3.6-5.0 80-99% B

For reactions involving microwave irradiation, a Biotage Initiator wasused.

Starting materials, reagents and solvents were obtained from commercialsuppliers and used without further purification unless otherwise stated.Unless otherwise stated, all compounds with chiral centres are racemic.Where reactions are described as having been carried out in a similarmanner to earlier, more completely described reactions, the generalreaction conditions used were essentially the same. Work up conditionsused were of the types standard in the art, but may have been adaptedfrom one reaction to another. The starting material may not necessarilyhave been prepared from the batch referred to. Compounds synthesised mayhave various purities ranging from for example 85% to 98%. However,calculations of number of moles and yield are generally not adjusted forthis.

Where applicable, the ratio of cis/trans isomers was assessed by NMRintegration. Characterisation of cis and trans was based on NMR shiftdata and coupling constants for the relevant H.

Abbreviations NMR Nuclear Magnetic Resonance

THF tetrahydrofuranDMSO dimethylsulfoxideDMF dimethylformamideDCM dichloromethaneDCE 1,2-dichloroethaneEDC 1-ethyl-3-(dimethylaminopropyl)carbodiimideEt₂O diethyl etherHOBt 1-hydroxybenzotriazoleMeCN/CH₃CN acetonitrileMeOH methanolDIPEA (Hunig's base)diisopropylethylaminenhex n-hexanec-hex cyclohexaneiso-hex iso-hexaneEtOAc ethyl acetateBoc/BOC t-butyloxycarbonyl

MDAP Mass-Directed Auto-Preparation

TLC thin layer chromatographyaq aqueouseq equivalentssat^(d) saturatedLC/MS liquid chromatography/mass spectrometryRt/rt/room temp room temperatureSM starting materialRM reaction mixtureFC flash chromatographyPS polymer supportedRB round bottomedCV column volumesPd/C palladium on charcoalPd₂ dba₃ Tris(dibenzylideneacetone)dipalladium (0)X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenylBINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl mCPBAmeta-chloroperoxybenzoic acidNaI sodium iodide

DESCRIPTION 1 cis/trans-Ethyl4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate. (D1)

Chloro(1,1-dimethylethyl)dimethylsilane (115 g; 0.76 mol) was added inportions over 1 hour to a solution of commercially available ethyl4-hydroxycyclohexanecarboxylate (118 g; 0.68 mol), imidazole (103 g;1.52 mol) and dimethylformamide (400 mL) stirred under an atmosphere ofargon. A small exotherm was observed resulting in the reaction mixturetemperature increasing to ˜40° C. The mixture was stirred at roomtemperature overnight then poured into 10% citric acid solution (2 L)and extracted with diethyl ether (2×800 mL). The ether extracts werewashed with water, brine and then dried (Na₂SO₄) and the solvent wasremoved to give the title compound as an oil (198.4 g)

¹H NMR δ (CDCl₃, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m),1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1H, m) 3.5(0.4H, m) 3.86 (1H, m) 4.1 (1H, m).

DESCRIPTION 2 cis/trans-Ethyl 4-(ethyloxy)cyclohexanecarboxylate. (D2)

cis/trans Ethyl4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D1,35 g, 122 mmol) was dissolved in CH₃CN (250 mL) and Et₃SiH (1.2 eq., 146mmol, 23 mL), BiBr₃ (4% mol, 4.9 mmol, 2.2 g) were added portionwise atroom temperature followed by acetaldehyde (1.2 eq., 8.2 mL) that wasslowly added at 25° C. The mixture was stirred at room temperature for 1hour. The mixture was subsequently poured onto an aqueous saturatedsolution of NaHCO₃ and the mixture obtained was then extracted withEtOAc (3×). Organics were combined, washed with brine, dried overNa₂SO₄, filtered and the solvent was evaporated to afford the crudemixture that was purified by silica chromatography (Biotage 65i column,EtOAc-nhex) to afford the title compound, 21 g, 87%.

¹H NMR δ (DMSO-d₆, 400 MHz): 1.1 (3H, m), 1.15 (3H, m), 1.492-3.212(assume 10H, set of broad signals and multiplets), 3.312 (2H, m), 4.041(2H, m).

DESCRIPTION 3 cis/trans-4-(Ethyloxy)cyclohexanecarboxylic acid. (D3)

Cis/trans-Ethyl 4-(ethyloxy)cyclohexanecarboxylate (D2, 21 g, 105 mmol)was dissolved in MeOH-THF (100 mL-100 mL) and NaOH (5 eq., 0.5 mol, 40mL, 12.5 N aqueous solution) was slowly added at room temperature. Themixture was stirred at room temperature overnight. The THF/MeOH was thenevaporated and the crude was washed with Et₂O. The aqueous phase wasacidified and extracted with EtOAc (2×); organics were dried overNa₂SO₄, filtered and the solvent was evaporated to afford the titlecompound as a pale-yellow oil, 17.3 g, 96%.

¹H NMR δ (DMSO-d₆, 400 MHz): 1.1 (3H, m), 1.3-3.201 (assume 10H, set ofbroad signals and multiplets), 3.417 (2H, m), 12.1 (1H, s broad).

DESCRIPTION 4 cis/trans-4-(Ethyloxy)-1-methylcyclohexanecarboxylic acid.(D4)

A stirred solution of diisopropylamine (2.3 eq., 0.231 mol, 33 mL) indry THF (400 mL) at −20° C. under argon was treated over 10 min with2.5M n-butyllithium in hexane (2.3 eq., 93 mL; 0.231 mol), then allowedto warm to 0° C. and stir for 15 mins. The mixture was re-cooled to −10°C. and treated over 10 min with a solution ofcis/trans-4-(ethyloxy)cyclohexanecarboxylic acid (D3, 17.3 g, 0.1 mol)in ˜50 mL of dry THF. The resulting yellow solution was heated at 50° C.for 2.5 hr, then cooled to 0° C. and treated with iodomethane (3 eq.,0.3 mol, 19 mL). The mixture was allowed to warm to room temperature andstir overnight. The mixture was cooled to 10° C., treated with 10%citric acid solution (200 mL), and then solvent evaporated to halfvolume (concentrated under vacuum). The residual mixture was dilutedwith water (200 mL) and extracted with Et₂O (2 x). The combined extractswere washed with water (150 mL×2), dried (Na₂SO₄), filtered andconcentrated under vacuum to leave the title compound as a yellow oil,16.2 g, 87%, a mixture of cis:trans isomers.

¹H NMR δ (DMSO-d₆, 400 MHz): 1.09 (assume 8H, m), 1.51 (3H, m), 1.70(1H, m), 1.78 (1H, m), 2.01 (1H, m), 3.19 (1/2H, m), 3.39 (2H, m), 3.61(1/2H, m), 12.2 (1H, s br).

DESCRIPTION 5 trans-4-(Ethyloxy)-1-methylcyclohexanecarboxylic acid.(D5)

cis/trans-4-(Ethyloxy)-1-methylcyclohexanecarboxylic acid (D4, 16.2 g,87.1 mmol) was dissolved in thionyl chloride (15 eq., 1.31 mol, ˜95 mL)at room temperature and it was subsequently refluxed at 85° C. for 4 hr.The mixture was then allowed to cool to room temperature and the thionylchloride was azeotropically evaporated with toluene. The residue wasdissolved in THF (100 mL), treated with a 5% aqueous solution of Na₂CO₃(500 mL) and stirred well at room temperature for 20 minutes. Theaqueous residue was washed with Et₂O (2×), then acidified and extractedwith EtOAc (3×). The combined extracts were dried (Na₂SO₄), filtered andconcentrated under vacuum to leave the title compound, 6.5 g, 40%.

¹H NMR δ (DMSO-d_(s), 400 MHz): 1.08 (6H, m), 1.51 (6H, m), 1.69 (2H,m), 3.33 (1H, m), 3.39 (2H, q), 12.1 (1H, s br).

DESCRIPTION 6 trans-4-(Ethyloxy)-1-isocyanato-1-methylcyclohexane. (D6)

A stirred solution of trans-4-(ethyloxy)-1-methylcyclohexanecarboxylicacid (D5, 5.5 g, 29.5 mmol) in toluene (120 mL) at room temperatureunder argon was treated with triethylamine (1.3 eq., 37.7 mmol, 5.3 mL)and diphenylphosphoryl azide (1 eq., 29.5 mmol, 6.4 mL) and heated at85° C. for 1 hr. The mixture was allowed to cool to room temperature,then treated with 1M NaOH solution (300 mL) and extracted with Et₂O(3×). The combined extract was dried (Na₂SO₄), filtered and concentratedunder vacuum to leave the title compound, 5 g, 94%.

¹H NMR δ (DMSO-d_(s), 400 MHz): 1.09 (3H, t), 1.33 (3H, s), 1.49-1.69(8H, m), 3.39 (2H, q), 3.48 (1H, m).

DESCRIPTION 7 [trans-4-(Ethyloxy)-1-methylcyclohexyl]amine monohydrochloride. (D7)

A solution of trans-4-(ethyloxy)-1-isocyanato-1-methylcyclohexane (D6,5.0 g, 27.3 mmol) in THF (100 mL) was treated with 5M aqueous HCl acid(5.5 eq., 150 mmol, 30 mL) and stirred at room temperature under argonovernight, then concentrated under vacuum. The residual semi-solid wastriturated with Et₂O to give a first batch of title compound as a whitesolid, 2.8 g. The mother liquors were evaporated, dissolved in THF again(50 mL) and treated with 5M aqueous HCl acid (15 mL) and the mixturestirred over a weekend at room temperature. The solvent was thenevaporated and the solid obtained was dried in the oven at 50° C. beforetrituration with Et₂O. This final trituration afforded further 646 mg oftitle compound.

¹H NMR δ (DMSO-d₆, 400 MHz): 1.08 (3H, t), 1.26 (3H, s), 1.38 (2H, m),1.62 (4H, m), 1.85 (2H, m), 3.24 (1H, m), 3.42 (2H, q), 8.09 (3H, br s).

DESCRIPTION 8 1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinone.(D8)

A stirred solution of [trans-4-(ethyloxy)-1-methylcyclohexyl]amine monohydrochloride (D7, 3.44 g, 17.8 mmol) in a mixture of ethanol (216 mL)and water (108 mL) at room temperature under argon was treated withpotassium carbonate (1.1 eq., 19.6 mmol, 2.7 g) followed by1-ethyl-1-methyl-4-oxopiperidinium iodide (D9, 1.5 eq., 26.7 mmol, 7.1g), then heated at 80° C. for 2 hours. The mixture was allowed to coolto room temperature then the aqueous residue was treated with sat.NaHCO₃ solution and extracted with dichloromethane (3×). The combinedextracts were dried (Na₂SO₄) and concentrated under vacuum to leave thecrude compound which was chromatographed on silica gel (Biotage 65icolumn) eluting with 0-10% MeOH/NH₃/DCM to afford the title compound,2.3 g, 54%.

¹H NMR δ (DMSO-d₆, 400 MHz): 0.86 (3H, s), 1.10 (3H, t), 1.42 (2H, m),1.54 (4H, m), 1.79 (2H, m), 2.30 (4H, t), 2.73 (4H, t), 3.38-3.43 (3H,t+m).

DESCRIPTION 9 1-Ethyl-1-methyl-4-oxopiperidinium iodide. (D9)

Iodomethane (65 mL; 1.00 mol) was added in portions to a solution of1-ethyl-4-piperidone (100 g; 0.79 mol) in acetone (1 L) at 20-30° C.(internal, ice cooling). After stirring for 3 h more the title compoundwas obtained by filtration, and washing with acetone (189 g).

DESCRIPTION 102-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)phenol.(D10)

Polymer supported sodium cyanoborohydride (489 mg, 0.997 mmol, 2.04mmol/g) was added to a solution of 2-aminophenol (52.2 mg, 0.478 mmol),1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8, 135 mg,0.564 mmol) and acetic acid (0.27 mL, 4.72 mmol) in dichloromethane (2.5mL). The mixture was heated by microwave at 100° C. for 10 min beforebeing filtered and concentrated by rotary evaporation to give a yellowoil. The residue was purified via chromatography (silica,dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) togive2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)phenol(D10, 91.6 mg, 54%), which was isolated in two batches, as a colourlesssolid.

M+H⁺ 333

DESCRIPTION 11 cis/trans-Ethyl 4-(propyloxy)cyclohexanecarboxylate.(D11)

Propionaldehyde (6.4 g) in acetonitrile (50 mL) was added over 30minutes to a solution of cis/trans ethyl4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D1,25.2 g), bismuth tribromide (4.4 g) and triethylsilane (17.5 mL) inacetonitrile (300 mL) and the mixture was stirred for a further 1.5hours. The solvent was partially removed then the residue was treatedwith ethyl acetate and saturated sodium bicarbonate solution. Theorganic layer was separated, washed with brine, dried with anhydroussodium sulphate and the solvent was removed to give the title compoundscontaminated with silicone residues (39.1 g).

DESCRIPTION 12 cis/trans-4-(Propyloxy)cyclohexanecarboxylic acid. (D12)

cis/trans-Ethyl 4-(propyloxy)cyclohexanecarboxylate (D11) (39.1 g), 40%w/w sodium hydroxide solution (150 mL), tetrahydrofuran (200 mL) andmethanol (150 mL) was stirred for approx. 72 hours. The solvent waspartially removed then the resulting mixture was treated with ethylacetate and water. The aqueous layer was separated, acidified withconcentrated hydrochloric acid and extracted with diethyl ether. Theether layer was washed with brine, dried with anhydrous sodium sulphateand the solvent was removed to give the title compounds as oil (15.42g).

DESCRIPTION 13 cis/trans-1-Methyl-4-(propyloxy)cyclohexanecarboxylicacid. (D13)

A stirred solution of diisopropylamine (24 mL, 0.17 mol) in THF (300 mL)at −20° C. under argon was treated over 10 mins with 2.5M n-butyllithiumin hexane (68 mL, 0.17 mol), then allowed to warm to 0° C. and stir for15 mins. The mixture was re-cooled to −10° C. and treated over 10 minswith a solution of 4-(propyloxy)cyclohexanecarboxylic acid (D12, 13.8 g,0.074 mol) in THF. The resulting yellow solution was heated at 50° C.for 2.5 hr, then cooled to 0° C. and treated with iodomethane (13.8 mL,0.22 mol). The mixture was allowed to warm to room temperature and stirfor 20 hr when a yellow precipitate had formed. The mixture was cooledto 10° C., treated with 10% citric acid solution (200 mL), thenconcentrated under vacuum to approx. 250 mL volume. The residual mixturewas diluted with water (200 mL) and extracted with Et₂O (3×250 mL). Thecombined extract was dried (Na₂SO₄) and concentrated under vacuum toleave a yellow oil (15.0 g) which was approx. 60:40 mixture of cis:transisomers.

DESCRIPTION 14 trans-1-Methyl-4-(propyloxy)cyclohexanecarboxylic acid.(D14)

cis/trans-1-Methyl-4-(propyloxy)cyclohexanecarboxylic acid (D13, 13 g,0.070 mol) was added to stirred thionyl chloride (50 mL), 0.68 mol) at10° C. and then allowed to warm to room temperature, followed by heatingat 85° C. for 3 hr. The mixture was concentrated under vacuum and theresidue concentrated twice with toluene to remove excess thionylchloride. The residue was dissolved in THF (100 mL), treated with dil.NaHCO₃ solution (250 mL) and stirred well at room temperature for 24 hr,followed by standing at room temperature for 3 days. The mixture fromthe same stage of a smaller scale reaction on 2 g ofcis/trans-1-methyl-4-(propyloxy)cyclohexanecarboxylic acid was combinedat this time. The combined mixture was concentrated under vacuum toapprox. 300 mL and the aqueous residue washed with Et₂O (2×120 mL), thenacidified with 2M HCl acid and extracted with EtOAc (2×150 mL). Thecombined extract was dried (Na₂SO₄) and concentrated under vacuum toleave the title compound as a pale yellow solid (5.1 g, 34%).

¹H NMR δ (CDCl₃, 400 MHz): 0.92 (3H, t), 1.24 (3H, s), 1.54-1.74 (8H,m), 1.78-1.88 (2H, m), 3.33-3.40 (3H, m). 1H not discernible fromspectrum.

DESCRIPTION 15 trans-1-Isocyanato-1-methyl-4-(propyloxy)cyclohexane.(D15)

A stirred solution of trans-1-methyl-4-(propyloxy)cyclohexanecarboxylicacid (D14, 5.1 g, 0.027 mol) in toluene (120 mL) at room temperatureunder argon was treated with triethylamine (4.9 mL, 0.035 mol) anddiphenylphosphoryl azide (5.8 mL, 0.027 mol) and heated at 85° C. for 1hr. The mixture was allowed to cool to room temperature, then treatedwith 1M NaOH solution (200 mL) and extracted with Et₂O (2×150 mL). Thecombined extract was dried (Na₂SO₄) and concentrated under vacuum toleave the title compound as a yellow oil (5.0 g, 100%).

¹H NMR δ (CDCl₃, 400 MHz): 0.91 (3H, t), 1.36 (3H, s), 1.50-1.60 (4H,m), 1.65-1.80 (6H, m), 3.33 (2H, t), 3.46-3.52 (1H, m).

DESCRIPTION 16 [trans-1-Methyl-4-(propyloxy)cyclohexyl]aminehydrochloride. (D16)

A solution of trans-1-isocyanato-1-methyl-4-(propyloxy)cyclohexane (D15,5.0 g, 0.027 mol) in THF (100 mL) was treated with 5M HCl acid (25 mL)and stirred at room temperature under argon for 20 hr, then concentratedunder vacuum and the residue azeotroped with toluene to remove traces ofwater. The residual semi-solid was triturated with Et₂O (120 mL) to givea solid, which was filtered off, washed with Et₂O and dried at 50° C.under vacuum to afford the title compound as a white solid (4.5 g, 85%).

¹H NMR δ (CDCl₃, 400 MHz): 0.91 (3H, t), 1.47 (3H, s), 1-45-1.70 (4H,m), 1.75-2.00 (6H, m), 3.52 (2H, t), 3.40-3.48 (1H, m), 8.38 (3H, br s).

DESCRIPTION 171-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinone. (D17)

A stirred solution of [trans-1-methyl-4-(propyloxy)cyclohexyl]aminehydrochloride (D16, 4.5 g, 0.022 mol) in a mixture of ethanol (100 mL)and water (60 mL) at room temperature under argon was treated withpotassium carbonate (3.31 g, 0.024 mol) followed by1-ethyl-1-methyl-4-oxopiperidinium iodide (D9, 8.91 g, 0.033 mol), thenheated at 80° C. for 2.5 hr. The mixture was allowed to cool,concentrated under vacuum to approx. 60 mL, then the aqueous residue wastreated with sat. NaHCO₃ solution and extracted with DCM (3×80 mL). Thecombined extract was dried (Na₂SO₄) and concentrated under vacuum toleave an orange oil (6.1 g), which was chromatographed on silica geleluting with 0-10% MeOH/DCM to afford the title compound as a yellow oil(3.45 g, 63%).

¹H NMR δ (CDCl₃, 400 MHz): 0.93 (3H, s+3H, t), 1.48-1.72 (8H, m),1.80-1.92 (2H, m), 2.41 (4H, t), 2.82 (4H, t), 3.35-3.45 (3H, t+m).

DESCRIPTION 182-({1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)phenol.(D18)

2-Aminophenol (43.1 mg, 0.395 mmol) was dissolved in dichloromethane(2.5 mL) and 1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinone(D17, 100 mg, 0.395 mmol), acetic acid (0.113 mL, 1.97 mmol), andpolymer supported sodium cyanoborohydride (387 mg, 0.789 mmol, 2.04mmol/g) were all added at rt. The mixture was reacted at 100° C. in themicrowave for 10 min. The mixture was then cooled to rt, filtered andconcentrated by rotary evaporation. The crude product was then purifiedvia chromatography (silica, dichloromethane to 0.5% ammonia/9.5%methanol/90% dichloromethane) to give2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)phenol(D18, 54.7 mg, 36% yield) as a white solid.

M+H⁺ 347

DESCRIPTION 19 3-Amino-4-hydroxybenzonitrile. (D19)

4-Hydroxy-3-nitrobenzonitrile (0.5 g, 3.05 mmol) was dissolved inethanol (20 mL) and methanol (10 mL), and Raney-Nickel (1 mL, 10%aqueous solution) was added at rt followed by hydrazine mono hydrate(0.296 mL, 6.09 mmol). The mixture was stirred at rt overnight. Themixture was then filtered through celite and concentrated by rotaryevaporation. The residue was purified via chromatography (silica,n-hexane to ethyl acetate) to give 3-amino-4-hydroxybenzonitrile (D19,200 mg, 49%) as an orange solid.

M+H⁺ 135

¹H NMR: δ (DMSO-d₆, 400 MHz) 4.99 (2H, br. s), 6.74 (1H, d, J 7.9),6.82-6.89 (2H, m), 10.23 (1H, br. s).

DESCRIPTION 203-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-hydroxybenzonitrile.(D20)

Polymer supported sodium cyanoborohydride (419 mg, 0.854 mmol, 2.04mmol/g) was added to a solution of 3-amino-4-hydroxybenzonitrile (D19,55.2 mg, 0.412 mmol),1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8, 123 mg,0.514 mmol) and acetic acid (120 μl, 2.10 mmol) in dichloromethane (2.5mL). The mixture was heated by microwave at 100° C. for 10 min beforebeing filtered and concentrated by rotary evaporation to give anorange/brown oil. The residue was purified via chromatography (silica,dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) togive3-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-hydroxybenzonitrile(D20, 96.9 mg, 59% yield) as a yellow oil.

M+H⁺ 358 DESCRIPTION 21 5-Fluoro-4-methyl-2-nitrophenol. (D21)

70% Nitric acid (0.759 mL, 8.42 mmol) was added dropwise to a solutionof 3-fluoro-4-methylphenol (966 mg, 7.66 mmol) in dichloromethane (25mL) at rt. The reaction was stirred for 30 min before being washed withwater. The aqueous layer was extracted with dichloromethane (1×) and thecombined organics were dried (Na₂SO₄) and concentrated by rotaryevaporation to give a yellow/orange solid. The residue was purified viachromatography (silica, dichloromethane to 0.5% ammonia/9.5%methanol/90% dichloromethane) to give 5-fluoro-4-methyl-2-nitrophenol(D21, 873 mg, 67% yield) as a yellow solid.

¹H NMR δ (CDCl₃, 400 MHz) 2.60 (3H, s), 6.80 (1H, d, J 10), 7.99 (1H,dd, J 10 and 0.8).

DESCRIPTION 22 2-Amino-5-fluoro-4-methylphenol. (D22)

5-Fluoro-4-methyl-2-nitrophenol (D21, 162 mg, 0.946 mmol) was reducedusing H-Cube™ hydrogenator (full H₂ mode, 25° C., 1 mL/min). Thereaction was concentrated by rotary evaporation to give2-amino-5-fluoro-4-methylphenol (D22, 117 mg, 88% yield) as a paleyellow solid.

¹H NMR δ (CDCl₃, 400 MHz) 2.13 (3H, s), 6.51 (1H, d, J 10), 6.61 (1H, d,J 7.6).

DESCRIPTION 232-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-5-fluoro-4-methylphenol.(D23)

Polymer supported sodium cyanoborohydride (439 mg, 0.896 mmol, 2.04mmol/g) was added to a solution of 2-amino-5-fluoro-4-methylphenol (D22,61.4 mg, 0.435 mmol),1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8, 105 mg,0.440 mmol) and acetic acid (0.12 mL, 2.10 mmol) in dichloromethane (2.5mL). The mixture was heated by microwave at 100° C. for 10 min and thenfor a further 10 min before being filtered and concentrated by rotaryevaporation to give a green oil. The residue was purified viachromatography (silica, dichloromethane to 0.5% ammonia/9.5%methanol/90% dichloromethane) to give2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-5-fluoro-4-methylphenol(D23, 128 mg, 72% yield) as a white solid.

M+H⁺ 365

DESCRIPTION 242-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-(methylsulfonyl)phenol.(D24)

Polymer supported cyanoborohydride (158 mg, 0.679 mmol, 4.3 mmol/g) wasadded to a solution of 2-amino-4-(methylsulfonyl)phenol (63.6 mg, 0.34mmol), 1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8,84.6 mg, 0.353 mmol) and acetic acid (0.1 mL, 1.75 mmol) intetrahydrofuran (2.5 mL). The mixture was heated by microwave at 100° C.for 30 min before being filtered and concentrated by rotary evaporationto give a pale yellow oil. The residue was purified via chromatography(silica, dichloromethane to 0.5% ammonia/9.5% methanol/90%dichloromethane) to give2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-(methylsulfonyl)phenol(D24, 93.3 mg, 67% yield) as a white solid.

¹H NMR δ (CDCl₃, 400 MHz) 1.10-1.22 (6H, m), 1.33-2.08 (10H, m),2.38-2.59 (2H, m), 2.90-3.13 (6H, m), 3.16-3.37 (2H, m), 3.41-3.52 (3H,m), 6.64 (1H, d, J 8), 7.09 (2H, m).

DESCRIPTION 252-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-(ethylsulfonyl)phenol.(D25)

2-Amino-4-(ethylsulfonyl)phenol (91 mg, 0.451 mmol) was dissolved intetrahydrofuran (3 mL) and1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8, 108 mg,0.451 mmol), polymer supported sodium cyanoborohydride (442 mg, 0.902mmol, 2.04 mmol/g), and acetic acid (0.129 mL, 2.26 mmol) were all addedat rt. The mixture was reacted at 100° C. in the microwave for 95 min.The mixture was then cooled to rt, filtered and concentrated to give2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-(ethylsulfonyl)phenol(D25, 211 mg, 66% yield) as a brown oil.

M+H⁺ 425

DESCRIPTION 264-Fluoro-2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)phenol.(D26)

2-Amino-4-fluorophenol (55.2 mg, 0.434 mmol) was dissolved indichloromethane (3 mL) and1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinone (D17, 110 mg,0.434 mmol), polymer supported sodium cyanoborohydride (426 mg, 0.868mmol, 2.04 mmol/g) and acetic acid (0.124 mL, 2.17 mmol) were all addedat rt. The mixture was reacted at 100° C. in the microwave for 10 min.The mixture was then cooled to rt, filtered and evaporated to give4-fluoro-2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)phenol(D26, 216 mg, 82% yield) as a brown solid.

M+H⁺ 365

DESCRIPTION 272-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-fluorophenol.(D27)

2-Amino-4-fluorophenol (74.0 mg, 0.582 mmol) was dissolved indichloromethane (3 mL) and1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8, 139 mg,0.582 mmol), polymer supported sodium cyanoborohydride (571 mg, 1.16mmol, 2.04 mmol/g) and acetic acid (0.167 mL, 2.91 mmol) were all addedat rt. The mixture was reacted at 100° C. in the microwave for 10 min.The mixture was then cooled to rt, filtered and concentrated by rotaryevaporation to give2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-fluorophenol(D27, 299 mg, 88% yield) as a brown oil.

M+H⁺ 351

DESCRIPTION 282-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-(methyloxy)phenol.(D28)

2-Amino-4-(methyloxy)phenol monohydrochloride (503 mg, 2.86 mmol) wastreated with saturated aqueous NaHCO₃ (50 mL) and the aqueous layer wasextracted with dichloromethane (2×). The combined organics were thendried (Na₂SO₄) and concentrated by rotary evaporation to give the freebase. The free base was then dissolved in dichloromethane (3 mL) and1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8, 99.2 mg,0.414 mmol), acetic acid (0.119 mL, 2.07 mmol) and polymer supportedsodium cyanoborohydride (406 mg, 0.829 mmol) were all added at rt. Themixture was reacted at 100° C. in the microwave for 10 min. The mixturewas then cooled to rt, filtered and concentrated by rotary evaporation.The crude product was then purified via chromatography (silica,dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) togive2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-(methyloxy)phenol(D28, 79.7 mg, 42% yield) as a brown solid.

M+H⁺ 363

DESCRIPTION 292-({1-[trans-4-(Ethyloxy)cyclohexyl]-4-piperidinyl}amino)-4-methylphenol. (D29)

2-Amino-4-methylphenol (56.1 mg, 0.456 mmol) was dissolved indichloromethane (3 mL) and1-[trans-4-(ethyloxy)cyclohexyl]-4-piperidinone (D66, 103 mg, 0.456mmol), polymer supported sodium cyanoborohydride (212 mg, 0.912 mmol,4.3 mmol/g) and acetic acid (0.13 mL, 2.28 mmol) were all added at rt.The mixture was reacted at 100° C. in the microwave for 10 min. Themixture was then cooled to rt, filtered and concentrated by rotaryevaporation to give2-({1-[trans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}amino)-4-methylphenol(D29, 215 mg, 92% yield) as a white solid.

M+H⁺ 333

DESCRIPTION 302-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-methylphenol.(D30)

Polymer supported sodium cyanoborohydride (592 mg, 1.21 mmol, 2.04mmol/g) was added to a solution1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8, 145 mg,0.604 mmol), 2-amino-4-methylphenol (79.9 mg, 0.649 mmol) and aceticacid (0.2 mL, 3.49 mmol) in dichloromethane (2.5 mL). The mixture washeated by microwave at 100° C. for 10 min before being filtered andconcentrated by rotary evaporation to give a yellow oil. The residue waspurified via chromatography (silica, dichloromethane to 0.5%ammonia/9.5% methanol/90% dichloromethane) to give2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-methylphenol(D30, 143 mg, 65% yield) as a white solid.

M+H⁺ 347

DESCRIPTION 312-Chloro-N-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-N-(2-hydroxy-5-methylphenyl)acetamide.(D31)

Chloroacetyl chloride (0.1 mL, 1.25 mmol) was added to a mixture of2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-methylphenol(D30, 163 mg, 0.471 mmol) in ethyl acetate (5 mL) and potassiumcarbonate solution (5 mL, 2.5 mmol, 0.5 M in water). The reaction wasstirred for 1 h and then the 2 phases were separated and the organicphase was dried (Na₂SO₄) and concentrated by rotary evaporation to give2-chloro-N-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-N-(2-hydroxy-5-methylphenyl)acetamide(D31, 186 mg, 93% yield) as a pale yellow oil.

M+H⁺ 423

DESCRIPTION 32 1,1-Dimethylethyl4-[(5-cyano-2-hydroxyphenyl)amino]-1-piperidinecarboxylate. (D32)

Polymer supported sodium cyanoborohydride (3531 mg, 7.20 mmol, 2.04mmol/g) was added to a solution of 3-amino-4-hydroxybenzonitrile (D19,477 mg, 3.56 mmol), 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (709mg, 3.56 mmol) and acetic acid (1 mL, 17.5 mmol) in tetrahydrofuran (10mL). The mixture was heated by microwave at 100° C. for 30 min and thenfor a further 30 min before being filtered and concentrated by rotaryevaporation to give 1,1-dimethylethyl4-[(5-cyano-2-hydroxyphenyl)amino]-1-piperidinecarboxylate (D32, 982 mg,3.09 mmol, 87% yield) as a yellow solid.

M−H⁺ 316

¹H NMR: δ (CDCl₃; 400 MHz) 1.32-1.53 (11H, m), 2.03 (2H, m), 2.86-3.14(2H, m), 3.41 (1H, m), 4.03 (2H, m), 6.77 (1H, d, J 1.8), 6.82 (1H, d, J8.0), 6.90 (1H, dd, J 8.0 and 1.8).

DESCRIPTION 33 1,1-Dimethylethyl4-(5-cyano-2-methylidene-1,3-benzoxazol-3(2H)-yl)-1-piperidinecarboxylate.(D33)

Hünig's base (1 mL, 5.73 mmol) was added to a solution of1,1-dimethylethyl4-[(5-cyano-2-hydroxyphenyl)amino]-1-piperidinecarboxylate (D32, 977 mg,3.08 mmol) in dichloromethane (20 mL) at rt under argon. The reactionwas cooled to 0° C. and triphosgene (373 mg, 1.26 mmol) was added. Thereaction was then stirred for 30 min at 0° C. and quenched withsaturated aqueous NaHCO₃ (20 mL) before being partitioned betweendichloromethane and water. The aqueous layer was extracted withdichloromethane (2×) and the combined organics were dried (Na₂SO₄) andconcentrated by rotary evaporation to give a yellow oil. The cruderesidue was purified via chromatography (silica, Biotage 40+S column,dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) togive 1,1-dimethylethyl4-(5-cyano-2-methylidene-1,3-benzoxazol-3(2H)-yl)-1-piperidinecarboxylate(D33, 1.22 g, 92% yield, 82% purity by LC-MS) as a yellow oil.

[M-O^(t)Bu] 270

¹H NMR: δ (CDCl₃; 400 MHz) 1.51 (9H, s), 1.93 (2H, m), 2.28 (2H, m),2.92 (2H, m), 4.28-4.44 (3H, m), 7.35 (1H, d, J 8.8), 7.48-7.54 (2H, m).

DESCRIPTION 342-oxo-3-(4-piperidinyl)-2,3-dihydro-1,3-benzoxazole-5-carbonitrilemonohydrochloride. (D34)

1,1-Dimethylethyl4-(5-cyano-2-oxo-1,3-benzoxazol-3(2H)-yl)-1-piperidinecarboxylate (D33,1.22 g, 2.84 mmol, 80% wt.) was dissolved in dichloromethane (20 mL) atrt to give a yellow solution and HCl (20 mL, 80 mmol, 4 M in1,4-dioxane) was added whereupon the mixture turned orange. The reactionwas stirred for 2 h (precipitate formed after 15 minutes). The reactionwas diluted with diethyl ether (20 mL) and filtered. The solid waswashed with diethyl ether (2×) and dried under high vacuum to give2-oxo-3-(4-piperidinyl)-2,3-dihydro-1,3-benzoxazole-5-carbonitrilemonohydrochloride (D34, 557 mg, 70% yield) as a pale pink solid.

[M+H]⁺ 244

¹H NMR δ (DMSO-d₆; 400 MHz) 2.01 (2H, m), 3.07 (2H, m), 3.44 (2H, m),4.54 (1H, m), 7.59 (1H, d, J 8.3), 7.70 (1H, dd, J 8.3 and 1.5), 8.07(1H, d, J1.5), 8.94 (2H, m). 2H obscured by solvent peak.

DESCRIPTION 353-[1-(1-Cyano-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile.(D35)

2-Oxo-3-(4-piperidinyl)-2,3-dihydro-1,3-benzoxazole-5-carbonitrilemonohydrochloride (D34, 254.4 mg, 0.909 mmol) was purified by SCX (5 g,eluting with MeOH followed by 2 M NH₃ in MeOH) to give the free base(225 mg). The free base was then dissolved in N,N-dimethylacetamide (10mL) at rt under argon. MgSO₄ (560 mg, 4.66 mmol),4-{[2-(methyloxy)ethyl]oxy}cyclohexanone (D61, 259 mg, 1.51 mmol) andacetone cyanohydrin (0.17 mL, 1.86 mmol) were added and the reaction washeated at 70° C. overnight under a gentle stream of argon. The mixturewas then cooled to rt, diluted with 1:1 dichloromethane:water (30 mL)and sonicated for 15 min. The phases were allowed to separate and theorganic phase was dried by filtering through a hydrostatic cartridge. Afurther 10 mL of dichloromethane was added to the aqueous phase and themixture stirred vigorously for 10 min. The 2 phases were again separatedand the organic phase was dried by filtering through a hydrostaticcartridge. The combined organic layer was concentrated by rotaryevaporation to give341-(1-cyano-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile(D35, 490 mg, 15% yield, 12% purity) as a yellow oil.

Isomer 1: [M-CN]⁺ 398; retention time 2.75.

Isomer 2: [M-CN]⁺ 398; retention time 2.85.

DESCRIPTIONS 36 and 374-Hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile.(D36) and4-Hydroxy-3-{[1-(cis-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile.(D37)

Methylmagnesium iodide (2.3 mL, 6.90 mmol, 3 M in diethyl ether) wasadded to a suspension of3-O-(1-cyano-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile(D35, 490 mg, 0.808 mmol, 70% wt.) in tetrahydrofuran (5 mL) at rt underargon. The reaction was diluted with a further portion oftetrahydrofuran (5.00 mL) and stirred for 2 h before being cooled to 0°C. and being quenched with saturated aqueous NH₄Cl (5 mL). The mixturewas partitioned between ethyl acetate and water and the aqueous layerwas extracted with ethyl acetate (2×). The combined organics were dried(Na₂SO₄) and concentrated by rotary evaporation to give an orange/yellowoil. The mixture was separated by high pH MDAP to give4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile(D36, 37.5 mg, 70% yield) as a colourless oil and4-hydroxy-3-{[1-(cis-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile(D37, 22.6 mg, 42% yield) as an off white solid.

Assignment of cis or trans geometry was by conversion to thebenzoxazolone and then use of distinctive chemical shift

trans: [M+H]⁺ 388; Rt=5.61

cis: [M+H]⁺ 388; Rt=7.07

DESCRIPTION 36 Alternative Procedure.4-Hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile.(D36)

Polymer supported cyanoborohydride (908 mg, 3.90 mmol, 4.3 mmol/g) wasadded to a solution of 3-amino-4-hydroxybenzonitrile (D19, 265 mg, 1.98mmol),1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone(D73, 526 mg, 1.95 mmol) and acetic acid (0.56 mL, 9.76 mmol) in THF (8mL). The mixture was heated by microwave at 100° C. for 1 h and then fora further 1 hour. The reaction was then filtered and concentrated byrotary evaporation to give a yellow/brown oil which was purified viaflash column chromatography (silica, Biotage 40+S column, DCM to 0.5%NH₃/9.5% MeOH/90% DCM) to give4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile(D36, 554 mg, 73%) as a cream solid.

LCMS: [M+H]⁺388

¹H NMR: δ (CDCl₃; 400 MHz) 1.04 (3H, s), 1.34-1.48 (2H, m), 1.50-1.77(6H, m), 1.81-1.98 (2H, m), 2.05-2.16 (2H, m), 2.33-2.48 (2H, m),3.04-3.29 (4H, m), 3.39 (3H, s), 3.51-3.61 (4H, m), 6.58 (1H, d, J 8.1),6.70 (1H, d, J 1.9), 6.85 (1H, dd, J 8.1 and 1.9).

DESCRIPTION 38 Bis(1,1-dimethylethyl)(4-methyl-2-nitrophenyl)propanedioate. (D38)

A stirred solution of di-tert-butyl malonate (1.5 mL, 6.70 mmol) inN,N-dimethylformamide (15 mL) at 0° C. under argon was treatedportionwise over 10 minutes with sodium hydride (276 mg of 60% oildispersion, 6.90 mmol) and stirred at 0° C. for 15 minutes beforeallowing to warm to room temperature over 1 hour. A white precipitatewas produced. The stirred mixture was cooled to 0° C. and treated with asolution of 4-fluoro-3-nitrotoluene (1.0 g, 6.45 mmol) inN,N-dimethylformamide (2 mL) and a deep purple colour was immediatelyformed. This mixture was stirred at room temperature for 28 hours thenheated at 70° C. for 6 hours. The mixture was cooled, then diluted withwater (100 mL) and extracted with Et₂O (2×50 mL). The combined extractwas washed with water (70 mL), dried (Na₂SO₄) and concentrated undervacuum. The residue was purified by chromatography on silica gel (40 g)eluting with toluene to afford the title compound as a yellow oil (660mg, 29%).

¹H NMR δ (CDCl₃, 400 MHz): 1.48-1.53 (18H, m), 2.43 (3H, s), 5.06 (1H,s), 7.40-7.48 (2H, m), 7.84 (1H, d).

DESCRIPTION 39 Bis(1,1-dimethylethyl)(2-amino-4-methylphenyl)propanedioate. (D39)

A solution of bis(1,1-dimethylethyl)(4-methyl-2-nitrophenyl)propanedioate (D38, 660 mg, 1.88 mmol) in ethylacetate (25 mL) was treated with 10% Pd/C (0.5 g) and shaken underhydrogen at atmospheric pressure and room temperature for 20 hours. Themixture was filtered through Kieselguhr and the filtrate concentratedunder vacuum to afford the title compound as a colourless oil (606 mg,100%).

¹H NMR δ (CDCl₃, 400 MHz): 1.40-1.52 (18H, m), 2.24 (3H, s), 4.03 (2H,br s), 4.43 (1H, s), 6.50-6.60 (2H, m), 7.04 (1H, d).

DESCRIPTION 40 Bis(1,1-dimethylethyl)[4-methyl-2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)phenyl]propanedioate.(D40)

A stirred solution of1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinone (D17, 165 mg,0.65 mmol) in dichloromethane (5 mL) at room temperature under argon wastreated with bis(1,1-dimethylethyl)(2-amino-4-methylphenyl)propanedioate (D39, 200 mg, 0.62 mmol), sodiumtriacetoxyborohydride (190 mg, 0.90 mmol) and acetic acid (1 drop) andmaintained at room temperature for 19 hours. Further1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinone (165 mg) andsodium triacetoxyborohydride (190 mg) were then added and the mixturestirred at room temperature for 10 days. The reaction mixture wastreated with Na₂CO₃ solution and extracted with dichloromethane.

The extract was dried (Na₂SO₄) and concentrated under vacuum to leave ayellow oil (340 mg) containing the title compound. This was used in thenext step without further purification.

DESCRIPTION 41 2-Fluoro-4-methyl-6-nitrophenol. (D41)

To 2-fluoro-4-methylphenol (500 mg, 3.96 mmol) in dichloromethane (5 mL)at room temperature was added dropwise nitric acid 70% (0.4 mL, 4.44mmol) [exotherm observed]. After 15 min more washed with water, dried,evaporated to give 2-fluoro-4-methyl-6-nitrophenol (400 mg, 2.337 mmol,59.0% yield) as a yellow solid.

DESCRIPTION 42 2-Fluoro-4-methyl-6-aminophenol (D42)

A solution of 2-fluoro-4-methyl-6-nitrophenol D41 (400 mg, 2.337 mmol)(D41) in ethanol (50 mL) was hydrogenated using a Pd/C cartridge in theH-cube™ hydrogenator at 1 mL/min and full hydrogen. Evaporation gave2-fluoro-4-methyl-6-aminophenol (250 mg, 1.771 mmol, 76% yield) as afawn solid.

DESCRIPTION 432-({1-[trans-4-Ethoxy-1-methylcyclohexyl]-4-piperidinyl}amino)-6-fluoro-4-methylphenol.(D43)

A mixture of 2-fluoro-4-methyl-6-aminophenol (60 mg, 0.425 mmol) (D42),1-[trans-4-ethoxy-1-methylcyclohexyl]-4-piperidinone (D8, 100 mg, 0.418mmol), polymer supported cyanoborohydride (450 mg, 0.918 mmol), aceticacid (0.14 mL, 2.448 mmol), and dichloromethane (2.5 mL) was heated inthe microwave reactor at 100° C. for 10 min, then filtered andevaporated. Chromatography (20 g silica, 0-10% 2M ammonia-methanol indichloromethane) gave2-({1-[trans-4-ethoxy-1-methylcyclohexyl]-4-piperidinyl}amino)-6-fluoro-4-methylphenol(100 mg, 0.274 mmol, 65.7% yield) as a foam.

DESCRIPTION 44 2,3-Difluoro-4-methyl-6-nitrophenol. (D44)

To 2,3-difluoro-4-methylphenol (1 g, 6.94 mmol) in dichloromethane at 0°C. was added nitric acid 70% (0.7 mL, 7.77 mmol). After 1 h at roomtemperature the solution was washed with water, dried and evaporated togive 2,3-difluoro-4-methyl-6-nitrophenol (1.2 g, 6.35 mmol, 91% yield)(D44) as yellow solid.

DESCRIPTION 45 2,3-Difluoro-4-methyl-6-aminophenol. (D45)

A solution of 2,3-difluoro-4-methyl-6-nitrophenol (1.2 g, 6.35 mmol)(D44) in ethanol (120 mL) was hydrogenated using a 10% Pd/C cartridge inthe H-cube™ hydrogenator at 1 mL/min and full hydrogen at 25° C.Evaporation gave 2,3-difluoro-4-methyl-6-aminophenol (1.0 g, 6.28 mmol,99% yield) as a fawn solid.

DESCRIPTION 462-({1-[trans-4-Ethoxy-1-methylcyclohexyl]-4-piperidinyl}amino)-5,6-difluoro-4-methylphenol.(D46)

A mixture of 2,3-difluoro-4-methyl-6-aminophenol (D45, 75 mg, 0.471mmol), 1-[trans-4-ethoxy-1-methylcyclohexyl]-4-piperidinone (D8, 100 mg,0.418 mmol), polymer supported cyanoborohydride (400 mg, 0.816 mmol),acetic acid (0.15 mL, 2.62 mmol), and dichloromethane (2.5 mL) washeated in the microwave reactor at 100° C. for 10 min, then filtered andevaporated. Chromatography on silica (20 g), eluting with 0-15% 2Mammonia in methanol-dichloromethane, gave6-({1-[trans-4-ethoxy-1-methylcyclohexyl]-4-piperidinyl}amino)-2,3-difluoro-4-methylphenol(110 mg, 0.288 mmol, 68.8% yield) as a white solid.

DESCRIPTION 47 1-[trans-1-Methyl-4-(methyloxy)cyclohexyl]-4-piperidinone(D47)

(i) cis/trans-1-Methyl-4-(methyloxy)cyclohexanecarboxylic acid

A stirred solution of diisopropylamine (16.1 mL, 115 mmol, 2.1 eq.) intetrahydrofuran (200 mL) at 0° C. under argon was treated with 2.5Mn-butyllithium in hexane (1.05 eq., 110 mmol, 44 mL) and it was thenstirred at the same temperature for 10 minutes. The mixture was thentreated with a solution of 4-(methyloxy)cyclohexanecarboxylic acid (1eq., 55 mmol, 8.7 g) in 50 mL of dry tetrahydrofuran. The resultingyellow solution was heated at 50° C. for 2 hr, then cooled to 0° C. andtreated with iodomethane (3 eq., 12 mL). The mixture was allowed to warmto room temperature and was stirred for 2 hr. The mixture waspartitioned between citric acid (10% aqueous solution) and Et₂O, the twophases were separated and the aqueous was extracted with Et₂O (2×).Organics were combined, dried (Na₂SO₄), filtered and concentrated undervacuum to leave a yellow solid (9.8 g) a mixture of cis:trans isomers.

¹H NMR δ (DMSO-d₆, 400 MHz): 1.08-2.09 (11H, cis/trans isomers), 3.07(0.5H, m single isomer), 3.19 (1.5H, s single isomer), 3.21 (1.5H, ssingle isomer), 3.61 (0.5H, s broad, single isomer), >12.5 (1H, s broad,cis/trans isomers).

(ii) trans-1-Methyl-4-(methyloxy)cyclohexanecarboxylic acid

cis/trans-1-methyl-4-(methyloxy)cyclohexanecarboxylic acid from part (i)(41.3 mmol, 7.7 g) was dissolved in thionyl chloride (15.3 eq., 631mmol, 46 mL). The mixture was refluxed at 90° C. for 4 hours. Thesolvent was evaporated and the crude product treated with toluene andconcentrated in vacuo. The residual brown oil was treated with 5%Na₋₂CO₃ solution (400 mL) and tetrahydrofuran (40 mL) and the mixturewas stirred at room temperature for 30 minutes. The aqueous solution waswashed with Et₂O (2×) and the aqueous phase was acidified with 2M HClacid and extracted with ethyl acetate (2×). The combined organics weredried over Na₂SO₄, filtered and the solvent was evaporated to afford thetitled compound (2.8 g, 40%).

¹H NMR δ (DMSO-d₆, 400 MHz): 1.09 (3H, s), 1.42 (2H, m), 1.49 (4H, m),1.70 (2H, m), 3.23 (4H, m), 3.34 (1H, s).

(iii) trans-1-Isocyanato-1-methyl-4-(methyloxy)cyclohexane

To a solution of trans-1-methyl-4-(methyloxy)cyclohexanecarboxylic acidfrom part (ii) (15.0 mmol, 2.8 g) in dry toluene (70 mL), Et₃N (1.3 eq.,19.6 mmol, 2.7 mL), and diphenylphosphoryl azide (1.0 eq., 15.0 mmol,3.2 mL) were added at room temperature. The mixture was refluxed at 80°C. for 2 hours. The mixture was cooled to room temperature and pouredonto 1M NaOH (70 mL); the aqueous solution was extracted with EtOAc(2×). The organics were combined dried over Na₂SO₄, filtered and thesolvent was evaporated to afford the crude compound. The crude productwas then purified by chromatography (EtOAc-n-hexane) on silica column toafford the title compound (1.33 g, 48%).

¹H NMR δ (DMSO-d₆, 400 MHz): 1.33 (3H, s), 1.61 (8H, m), 3.20 (3H, s)3.36 (1H, m).

(iv) trans-1-Methyl-4-(methyloxy)cyclohexanamine monohydrochloride

To a solution of trans-1-isocyanato-1-methyl-4-(methyloxy)cyclohexanefrom part (iii) (7.27 mmol, 1.33 g) in THF (30 mL), concentrated HCl (6mL) was added at room temperature. The mixture was stirred for 4 hoursat room temperature and concentrated HCl (a few drops) was added. Thereaction was left overnight and the solvent evaporated to afford thetitle compound (0.9 g, 69%).

¹H NMR δ (DMSO-d₆, 400 MHz): 1.26 (3H, s), 1.39 (2H, m), 1.63 (4H, m),1.87 (2H, m), 3.16 (1H, m), 3.22 (3H, s), 8.22 (3H, br s).

(v) 1-[trans-1-Methyl-4-(methyloxy)cyclohexyl]-4-piperidinone (D47)

trans-1-Methyl-4-(methyloxy)cyclohexanamine monohydrochloride from part(iv) (7.69 mmol, 1.1 g), 1-ethyl-1-methyl-4-oxopiperidinium iodide (D9,1.7 eq., 13.1 mmol), 3.5 g, K₂CO₃ (1.5 eq., 11.5 mmol, 1.5 g), water (40mL) and ethanol (80 mL) were refluxed at 80° C. until the startingmaterial was not observed on TLC. The mixture was partitioned betweenNaHCO₃ and dichloromethane. Some product was lost due to mechanicalspillage. The work up was repeated. The crude product was then purifiedby chromatography (MeOH—NH₃-dichloromethane) on silica column to affordthe title compound (650 mg, 35%).

¹H NMR δ (DMSO-d₆, 400 MHz) 0.85 (3H, s), 1.50 (6H, m), 1.76 (2H, m),2.30 (4H, t), 2.72 (4H, t), 3.21 (3H, s), 3.27 (1H, m).

DESCRIPTION 484-Methyl-2-({1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}amino)phenol.(D48)

Macroporous triethylammonium triacetoxyborohydride (1.0 g, 2.0 mmol/g)was added to a solution of 2-amino-4-methylphenol (86 mg) and1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinone (D47, 120 mg)in dry THF (3.0 mL) in a 5 mL microwave vial. The resulting suspensionwas heated to 100° C. for 30 min. After cooling the reaction was dilutedwith DCM and partitioned into NaHCO₃ (sat^(d) aq), the organic layersseparated, dried over MgSO₄, filtered and the solvent removed underreduced pressure to afford essentially pure product, 174 mg.

(M+H)⁺333.

DESCRIPTION 492-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4,6-difluorophenol.(D49)

2-Amino-4,6-difluorophenol (100 mg, 0.689 mmol),1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8, 127 mg,0.530 mmol), macroporous triethylammonium methylpolystyrenetriacetoxyborohydride (182 mg, 0.440 mmol) and 10% acetic acid intetrahydrofuran (3 mL) were combined in a 5 mL microwave vial, sealedand heated at 110° C. for 30 min. LC/MS showed the reaction to beincomplete. The reaction mixture was heated for a further 30 min at 110°C., but the reaction had not progressed any further. The reactionmixture was filtered, then diluted with dichloromethane (10 mL). Thesolution was washed with saturated aqueous sodium bicarbonate (12 mL),dried and evaporated to give a brown gum. Recrystallisation from hexaneand diethyl ether failed to purify the product. The product solution wasevaporated to give the title compound as a brown oil (175 mg), which wasestimated as being 30% pure by LC/MS. The crude material was carriedforward without further purification. (M+H)⁺=369.

DESCRIPTION 502-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-[(trifluoromethyl)oxy]phenol.(D50)

1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8; 113 mg,0.472 mmol) was dissolved in dichloromethane (DCM) (2.5 mL) and aceticacid (0.250 mL) and 2-amino-4-(trifluoromethoxy)phenol (109 mg, 0.567mmol) was added, followed by macroporous triethylammoniummethylpolystyrene cyanoborohydride (409 mg, 0.944 mmol). The reactionmixture was heated in a microwave reactor at 100° C. for 15 min. Thereaction mixture was diluted with DCM (12.5 mL) and washed with sodiumbicarbonate solution (15 mL). The organic layer was dried with magnesiumsulphate to give the title compound as a brown solid (102 mg), which wasestimated as being 20% pure by LC/MS. The crude material was carriedforward without further purification.

(M+H)⁺=417.

DESCRIPTION 512-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4,5-difluorophenolacetate. (D51)

1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8, 99 mg,0.414 mmol) was dissolved in dichloromethane (2.5 mL) and acetic acid(0.250 mL) and 2-amino-4,5-difluorophenol (72.0 mg, 0.496 mmol) wasadded, followed by macroporous triethylammonium methylpolystyrenecyanoborohydride (179 mg, 0.414 mmol). The reaction mixture was heatedin a microwave reactor at 100° C. for 10 min. The reaction mixture wasfiltered and evaporated to dryness to give the title compound as a brownoil (253 mg), with residual acetic acid. The crude material was carriedforward without further purification.

(M−H)⁺=367.

¹H NMR δ (CDCl₃): 1.19 (3H, m), 1.34 (4H, m), 1.90 (2H, m), 2.02-2.07(equivalent to 20H, br. m., contains acetic acid contaminant), 2.82 (1H,br. s), 3.28 (1H, s), 3.45-3.54 (3H, br. m), 6.32 (1H, m), 6.70 (1H, m).

DESCRIPTION 52 2-Amino-4-(trifluoromethyl)phenol. (D52)

A solution of 2-nitro-4-(trifluoromethyl)phenol (100 mg, 0.483 mmol) inethanol (10 mL) was pumped through an H-cube™ hydrogenator CatCart(Pd/C, 30×4 mm) at a flow rate of 1 mL/min at 40° C. and 40 psi, toppingup the solution with methanol (10×1 mL) when it was running low. Thecollected solution was evaporated to dryness to give an off-white solid(88 mg, assume quantitative yield). The material was carried forwardwithout further purification.

(M⁺=178.

¹H NMR δ (CDCl₃): 6.76 (1H, d, J=8.4 Hz), 6.94 (1H, d, J=8.4 Hz), 6.98(1H, s).

DESCRIPTION 532-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-(trifluoromethyl)phenolacetate. (D53)

1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8, 99 mg,0.414 mmol) was dissolved in dichloromethane (2.5 mL) and acetic acid(0.250 mL) and 2-amino-4-trifluoromethylphenol (D52, 88 mg, 0.497 mmol)was added, followed by macroporous triethylammonium methylpolystyrenecyanoborohydride (179 mg, 0.414 mmol). The reaction mixture was heatedin a microwave reactor at 100° C. for 15 min. The reaction mixture wasfiltered and evaporated thoroughly to give the title compound as ayellow oil (225 mg), with residual acetic acid. The crude material wascarried forward without further purification.

(M+H)⁺=401.

¹H NMR δ (CDCl₃): 1.19 (3H, m), 1.35 (3H, br. m), 1.88 (2H, m),2.05-2.07 (equivalent to 15H, m, contains acetic acid contaminant), 2.17(2H, m), 2.82 (1H, br. m), 3.36 (1H, br. m), 3.40 (1H, br. m), 3.52 (3H,br. m), 6.67 (1H, s), 6.80-6.93 (2H, m).

DESCRIPTION 54 bis(1,1-Dimethylethyl)[4-methyl-2-({1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}amino)phenyl]propanedioate.(D54)

1-[trans-1-Methyl-4-(methyloxy)cyclohexyl]-4-piperidinone D47 (0.8 eq.,0.25 mmol, 56 mg) and bis(1,1-dimethylethyl)(2-amino-4-methylphenyl)propanedioate D39 (1 eq., 0.31 mmol, 100 mg)were dissolved in isopropyl acetate (4 mL) and trifluoroacetic acid (2eq., 0.62 mmol, 45 microlitres) was added at Rt. NaBH(OAc)₃ (1.4 eq.,0.43 mmol, 92 mg) was then added at Rt and the mixture was stirred at Rtfor 3 hours. The mixture was then diluted with water, basified to pH=10(2M aq. NaOH) and it was extracted with EtOAc (3 x); organics werecombined, dried (Na₂SO₄), concentrated under vacuum and the residuechromatographed (12M amino column, EtOAc-n-hexane) to afford 100 mg of amixture containing the desired product that was used for the next step.

MH⁺=531.

DESCRIPTION 554-Hydroxy-3-({1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}amino)benzonitrile.(D55)

3-Amino-4-hydroxybenzonitrile (D19) (100 mg, 0.746 mmol) was dissolvedin dichloromethane (DCM) (4 mL) and1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinone D47 (336 mg,1.491 mmol), acetic acid (0.064 mL, 1.118 mmol), polymer supportedsodium cyanoborohydride (520 mg, 2.237 mmol) were all added at roomtemperature. The mixture was reacted at 90° C. in the microwave. Samplewas then cooled to Rt, purified on 5 g SCX column first and then bychromatography (40S silica cartridge, MeOH—NH₃-DCM) to afford the titlecompound, 70%.

MH⁺=344

DESCRIPTION 56 bis(1,1-Dimethylethyl)[2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-methylphenyl]propanedioate.(D56)

1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8) (1 eq.,0.38 mmol, 90 mg) and bis(1,1-dimethylethyl)(2-amino-4-methylphenyl)propanedioate (D39) (1.3 eq., 0.5 mmol, 158 mg)were dissolved in isopropyl acetate (3 mL) and trifluoroacetic acid (2.5eq., 0.95 mmol, 68 microlitres) were added at Rt; NaBH(OAc)₃ (1.7 eq.,0.65 mmol, 138 mg) was then added at Rt and the mixture was stirred atRt for 3 hours. The mixture was then diluted with water, basified topH=10 (2M aq. NaOH) and it was extracted with EtOAc (3 x); organics werecombined, dried (Na₂SO₄), concentrated under vacuum and the residuechromatographed (12M amino column, EtOAc-n-hexane) to afford 134 mg of amixture containing the desired product that was used for the next step.

MH⁺=545.

DESCRIPTION 572-({1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)-4-(methylsulfonyl)phenol.(D57)

Polymer supported cyanoborohydride (98 mg, 0.421 mmol) was added to asolution of 2-amino-4-(methylsulfonyl)phenol (39.4 mg, 0.210 mmol),1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinone (D17, 54.8 mg,0.216 mmol) and acetic acid (0.06 mL, 1.05 mmol) in tetrahydrofuran (2.5mL). The mixture was heated by microwave at 100° C. for 30 min and thenfor a further 30 min before a further solution of1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinone (35.1 mg) intetrahydrofuran (0.5 mL) was added and the reaction heated for another30 min. The mixture was then filtered and concentrated by rotaryevaporation to give a pale yellow solid. The residue was purified viachromatography (silica, dichloromethane to 0.5% ammonia/9.5%methanol/90% dichloromethane) to give2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)-4-(methylsulfonyl)phenol(D57, 31.4 mg, 0.074 mmol, 35% yield) as an off-white solid.

MH⁺=425

DESCRIPTION 583-[2-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-methylphenyl]propanoicacid. (D58)

A mixture of ethyl3-[2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-methylphenyl]propanoateD144 (80 mg, 0.186 mmol) and LiOH (15.59 mg, 0.372 mmol) in methanol (2mL) and water (2.000 mL) was heated to reflux for 4 hr. LC/MS of themixture indicated no SM to be present and a product with the desiredmol. wt to be the main component in the RM. The mixture was treated with2N HCl to adjust the pH to 4; the mixture was concentrated to dryness toafford a yellow gum, 94 mg, >100%, which was used without furtherpurification.

LC/MS 403 (MH⁺), 401(M−H).

DESCRIPTION 59a 1,4-Dioxaspiro[4.5]decan-8-ol. (D59)

1,4-Dioxaspiro[4.5]decan-8-one (64 mmol, 10 g) was dissolved in ethanol(125 mL) and treated with NaBH₄ (1.2 eq., 76.8 mmol, 2.9 g), at 0° C.portionwise and the mixture was stirred at room temperature for 1 hour.Reaction was quenched with NaOH (25 mL, 2N aqueous solution). Theaqueous solution was extracted with dichloromethane (2×). The organicswere combined, dried over Na₂SO₄, filtered and the solvent wasevaporated to afford the title compound, 8.3 g, 82%, as a colourlessoil.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.44 (4H, m), 1.64 (4H, m), 3.54 (1H, dbroad), 3.82 (4H, m), 4.48 (1H, d).

DESCRIPTION 59b Scale-up procedure. 1,4-Dioxaspiro[4.5]decan-8-ol. (D59)

1,4-Dioxaspiro[4.5]decan-8-one (60 g, 384 mmol) was dissolved inmethanol (600 mL) under Argon, then sodium borohydride (15.99 g, 423mmol) was added portionwise (the addition was exothermic and a huge gasevolution was observed). The resulting mixture was stirred for 30 min.The reaction was quenched with water (200 mL) and stirred for 10 min.Solvent was removed under reduced pressure and the residue taken-up withDCM (600 mL) and water (300 mL). Phases were separated then the aqueousphase extracted with DCM (1×600 mL). Combined organic phases were driedon Na₂SO₄ and concentrated under vacuum to obtain title material (58 g;95%) as colourless oil.

¹H NMR δ (CDCl₃, 400 MHz): 1.64 (4H, m), 1.87 (4H, m), 3.83 (1H, m),3.97 (4H, dt).

DESCRIPTION 60a 8-{[2-(Methyloxy)ethyl]oxy}-1,4-dioxaspiro[4.5]decane.(D60)

1,4-Dioxaspiro[4.5]decan-8-ol (D59, 10 g, 58 mmol) was dissolved in 200mL of dry DMF and NaH (60% dispersion in mineral oil, 1.01 eq., 58.7mmol, 2.3 g) was added at 0° C.

The mixture was stirred at the same temperature for 30 min and1-bromo-2-(methyloxy)ethane (1.5 eq., 87 mmol, 8.2 mL) was addedfollowed by NaI (cat, 500 mg) at 0° C. The mixture was stirred at Rtovernight. The mixture was then gently warmed to 40° C. and stirredovernight. The mixture was then quenched with MeOH, diluted with waterand extracted with EtOAc (3×). Organics were diluted with hexane andextracted with brine and water respectively (2×). Organics were thendried over Na₂SO₄, filtered and the solvent was evaporated to afford 3.7g of crude product that was purified by silica chromatography (40 Mcolumn, EtOAc-nhex) to afford 1.6 g of the title compound, 12%.

¹H NMR δ (CDCl₃, 400 MHz): 1.51-1.56 (2H, m), 1.69-1.87 (6H, m), 3.40(3H,s), 3.43 (1H, m), 3.54 (2H, m), 3.59 (2H, m), 3.93 (4H, m).

DESCRIPTION 60b Scale-up procedure.8-{[2-(Methyloxy)ethyl]oxy}-1,4-dioxaspiro[4.5]decane. (D60)

Two different batches of material were reacted separately and thenworked up together. In a 1 L round-bottomed flask1,4-dioxaspiro[4.5]decan-8-ol D59 (45 g, 284 mmol) was dissolved indimethyl sulfoxide (DMSO) (320 mL) to give a colourless solution.Potassium hydroxide (64 g, 1138 mmol) was added and the mixture wasallowed to stir under argon for 20 minutes then a catalytic amount ofsodium iodide was added. 2-Bromoethyl methyl ether (106 mL, 1138 mmol)was added dropwise keeping the internal temperature below +35° C. andthe mixture was allowed to stir at room temperature overnight. Thereaction was 80% complete by TLC after 5 hours. A further 32 g ofpotassium hydroxide and 54 mL of 2 bromoethyl methyl ether were addedconsequently and the reaction was allowed to stir at room temperaturefor 72 h.

In a similar way, in a 2 L round-bottomed flask1,4-dioxaspiro[4.5]decan-8-ol D59 (65.6 g, 415 mmol) was dissolved indimethyl sulfoxide (DMSO) (400 mL) to give a colourless solution.Potassium hydroxide (93.3 g, 1659 mmol) was added and the mixture wasallowed to stir under argon for 20 minutes then a catalytic amount ofNaI was added. 2-bromoethyl methyl ether (156 mL, 1659 mmol) was addeddropwise keeping the internal temperature below +35° C. and the mixturewas allowed to stir at room temperature overnight. After 5 h, reactionwas 80% complete by TLC. Potassium hydroxide (46.7 g) and 2-bromoethylmethyl ether (78 ml) were added and the reaction allowed to stir at rtfor a further 72 h.

The two reaction mixtures were combined and the overall resultingmixture was carefully portionwise added to a well stirred mixture of 1 Lof water and 2 L of diethyl ether. The aqueous layer was back extractedwith diethyl ether (2×500 mL). The organic phase was dried overanhydrous Na₂SO₄, filtered and concentrated to obtain 210 g of an oilresidue that was purified via Biotage® 75 L SiO₂ column eluting with 8/2c-hex/EtOAc. Collected fractions were evaporated under vacuum to affordtitle material (155.3 g; 102% uncorrected) as yellow oil.

¹H NMR δ (CDCl₃, 400 MHz): 1.55 (2H, m), 1.80 (6H, m), 3.40 (3H, s),3.44 (1H, m), 3.62-3.53 (4H, m), 3.95 (4H, d t).

DESCRIPTION 61a 4-{[2-(Methyloxy)ethyl]oxy}cyclohexanone. (D61)

8-{[2-(Methyloxy)ethyl]oxy}-1,4-dioxaspiro[4.5]decane (D60) (1.6 g, 7mmol), was dissolved in 20 mL of THF and HCl (25 eq., 5M, 35 mL) wasadded at Rt. The mixture was stirred at Rt for 5 hr. THF was thenevaporated and the aqueous was extracted with dichloromethane (2×).Organics were washed once with water, dried over Na₂SO₄, filtered andthe solvent was evaporated to afford the title compound, 1.3 g, completeconversion as a pale yellow oil.

¹H NMR δ (CDCl₃, 400 MHz): 1.92-2.00 (2H, m), 2.10-2.14 (2H, m),2.23-2.30 (2H, m), 2.55-2.63 (2H, m), 3.41 (3H, s), 3.58 (2H, m), 3.64(2H, m), 3.76 (1H, m).

DESCRIPTION 61b Scale-up procedure.4-{[2-(Methyloxy)ethyl]oxy}cyclohexanone. (D61)

In a 10 L round-bottomed flask8-{[2-(methyloxy)ethyl]oxy}-1,4-dioxaspiro[4.5]decane D60 (151 g, 700mmol) was dissolved in tetrahydrofuran (THF) (3000 mL) to give acolourless solution. 3M hydrochloric acid (2333 mL, 7000 mmol) wasadded. Reaction was allowed to stir at room temperature overnight. Theorganic solvent was partially evaporated under vacuum and then theaqueous layer was back extracted with DCM (3×500 mL). The organic phasewas dried over Na₂SO₄, filtered and concentrated to obtain 121 g ofcrude material as yellow oil. The crude product was purified by Biotage®75 L SiO₂ column eluting with c-hex/EtOAc 8/2 to get title material (76g; 63%).

¹H NMR δ (CDCl₃, 400 MHz): 1.98 (2H, m), 2.11 (2H, m), 2.28 (2H, m),2.60 (2H, m), 3.41 (3H, s), 3.59 (2H, m), 3.68 (2H, m), 3.77 (1H, m).

DESCRIPTION 62 trans-N-(4-Hydroxycyclohexyl)phthalimide. (D62)

N-Ethoxycarbonylphthalimide (100 g; 0.46 mol) was added to a mixture oftrans-4-hydroxycyclohexylamine hydrochloride (69 g; 0.46 mol), potassiumcarbonate (158 g; 1.15 mol) and water (1 L) at room temperature. Afterstirring for 3 h the title compound (95 g) was isolated by filtration,washing with water then ethyl acetate.

DESCRIPTION 63trans-N-(4-tert-Butyldimethylsilyloxycyclohexyl)phthalimide. (D63)

tert-Butyldimethylsilyl chloride (60 g; 0.39 mol) was added in portionsto a mixture of trans N-(4-hydroxycyclohexyl)phthalimide (D62, 95 g;0.39 mol), imidazole (55 g; 0.78 mol), and DMF (200 mL) at 20-30° C.(internal, ice cooling). After stirring for 3 h more at 40° C. themixture was partitioned between water/hexane. Drying and evaporation ofthe organic layer gave the title compound (92 g) crystallised frompentane.

DESCRIPTION 64 trans-N-(4-Ethoxycyclohexyl)phthalimide (D64)

Acetaldehyde (10 mL; 0.17 mol) in acetonitrile (50 mL) was added over 30minutes to a solution oftrans-N-(4-tert-butyldimethylsilyloxycyclohexyl)phthalimide (D63; 50.0g; 0.14 mol), bismuth tribromide (6.7 g; 0.015 mol) and triethylsilane(27 mL; 0.18 mol) in acetonitrile (500 mL) stirred at ice bathtemperature and the mixture was allowed to warm to room temperatureovernight. The mixture was filtered and the resulting grey solid andfiltrate were worked up separately. The filtrate was evaporated andtreated with hexane to give the title compound as a white solid (16.35g). The grey solid was washed with dichloromethane, the dichloromethaneextract was evaporated and the residue was stirred with hexane (200 mL)to give a second crop of the title compound as a white solid (17.47 g).

DESCRIPTION 65 trans-4-Ethoxycyclohexylamine (D65)

A solution of trans-N-(4-ethoxycyclohexyl)phthalimide (D64, 16.35 g),hydrazine hydrate (12 mL) in ethanol (300 mL) and methanol (200 mL) wasstirred at reflux for 3 hours. The solvent was removed to give a slurry,which was treated with diethyl ether and filtered. The filtrate wasevaporated to afford the title compound as a viscous oil contaminatedwith ether (8.16 g).

DESCRIPTION 66 trans-1-(4-Ethoxycyclohexyl)-4-piperidone (D66)

A mixture of 1-ethyl-4-piperidone methiodide (D9, 27 g),trans-4-ethoxycyclohexylamine (D65, 8.16 g, 0.065 mol), potassiumcarbonate (13.5 g), water (100 mL), and ethanol (200 mL) was heated for3 hours at 80° C., then cooled overnight. The mixture was partitionedwith aqueous sodium bicarbonate and dichloromethane. The dichloromethanelayer was separated, washed with brine and solvent removed to give thetitle compound as an amber coloured oil (13.2 g).

DESCRIPTION 67 2-Methylpropyl 1-methyl-4-oxocyclohexanecarboxylate.(D67)

2-(Trimethylsilyloxy)buta-1,3-diene (40 g, 281 mmol) was weighed into aTeflon™ microwave container. Isobutyl methacrylate (50.8 mL, 317 mmol)was added followed by 4,4′-methylenebis(2,6-di-tert-butylphenol) (0.5 g,1.177 mmol), finally 1-butyl-3-methylimidazolium hexafluorophosphate(0.5 mL) was added, the vessel transferred to the Advancer microwave andheated for 4 hr (normal absorption, no fixed hold time, 190° C.). After1 hr 20 min an error message was seen for the temperature probe, theerror was cleared and heating was continued for a further hour. At thistime the software had frozen forcing a shutdown at the mains. Thereaction mixture was allowed to cool to RT. Tetrahydrofuran (THF) (200mL) was added and the solution transferred to a round bottomed flask. 2MHCl was added and the reaction mixture left to stir overnight. DCM wasadded to the reaction mixture, whereupon an emulsion formed. An attemptto filter this was unsuccessful, and the mixture was left to standovernight. The organic layer was separated, dried (Na₂SO₄) andevaporated to give a sticky oil. Flash column chromatography, elutingwith ethyl acetate/isohexane gave 2-methylpropyl1-methyl-4-oxocyclohexanecarboxylate as a yellow oil (12.74 g, 60.0mmol, 21.35% yield).

DESCRIPTION 68 Isobutyl1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylate. (D68)

A solution of isobutyl 1-methyl-4-oxocycylohexanecarboxylate (D67, 12.7g, 59.8 mmol), t-butyl dimethyl 2-methoxyethoxy silane (11.4 g, 59.9mmol), and anhydrous ferric chloride (250 mg, 1.541 mmol) inacetonitrile (150 mL) at 0° C. was treated with triethylsilane (12 mL,75 mmol). The mixture was stirred for 1 h at room temperature, thenpartitioned between saturated sodium bicarbonate and dichloromethane,and the organic layer was dried and evaporated to give isobutyl1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylate (27 g, 49.6 mmol, 83%yield) as a cis/trans mixture containing one equivalent oft-butyldimethyl triethyl siloxane.

DESCRIPTION 69 1-Methyl-4-(2-methoxyethoxy)cyclohexanecarboxylic acid.(D69)

A mixture of isobutyl 1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylate(D68, 27 g, 49.6 mmol), 1,4-dioxane (100 mL) and 3M aqueous sodiumhydroxide (100 mL, 300 mmol) was heated at 100° C. for 18 h then cooledand partitioned between water and diethyl ether. The aqueous phase wasacidified and extracted with ethyl acetate to give the desired product.Unreacted starting material remained in the ether wash, so the ether wasevaporated and the residue dissolved in a mixture of THF (100 mL),methanol (100 mL), and 6M aqueous sodium hydroxide (100 mL) and heatedat 65° C. for 18 h then worked up as before to give additional product,which was combined to give1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylic acid (9.5 g, 43.9mmol, 89% yield) as a pale yellow oil.

DESCRIPTION 70 trans 1-Methyl-4-(2-methoxyethoxy)cyclohexanecarboxylicacid. (D70)

A solution containing 1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylicacid (D69, 9.5 g, 43.9 mmol), thionyl chloride (50 mL, 685 mmol), andtoluene (25 mL) was heated at 90° C. for 4 h then cooled and evaporated.The residue was stirred with aqueous sodium bicarbonate for 30 min thenwashed with diethyl ether. Acidification and extraction with ethylacetate gave trans 1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylicacid (3.2 g, 14.80 mmol, 33.7% yield) as an oil.

DESCRIPTION 71 trans 1-Methyl-4-(2-methoxyethoxy)cyclohexyl isocyanate.(D71)

A mixture of trans 1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylicacid (D70, 3.3 g, 15.26 mmol), diphenylphosphoryl azide (3.4 mL, 15.75mmol), triethylamine (4.0 mL, 28.6 mmol), and toluene (50 mL) was heatedat 100° C. for 1 h, then cooled and washed with water to give trans1-methyl-4-(2-methoxyethoxy)cyclohexyl isocyanate (3.2 g, 15.00 mmol,98% yield) as a mobile oil.

DESCRIPTION 72 trans 1-Methyl-4-(2-methoxyethoxy)cyclohexylaminehydrochloride. (D72)

A mixture of trans 1-methyl-4-(2-methoxyethoxy)cyclohexyl isocyanate(D71, 3.2 g, 15.00 mmol), 5M hydrochloric acid (50 mL, 250 mmol), andTHF (50 mL) was stirred at room temperature for 18 h then evaporated togive trans 1-methyl-4-(2-methoxyethoxy)cyclohexylamine hydrochloride(3.5 g, 15.64 mmol, 104% yield) as a pale brown foam.

DESCRIPTION 731-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone.(D73)

A solution of trans 1-methyl-4-(2-methoxyethoxy)cyclohexylaminehydrochloride (D72, 3.5 g, 15.64 mmol) in ethanol (80 mL) and water (40mL) was treated with potassium carbonate (3.0 g, 21.71 mmol). Themixture was heated to 80° C. and then a solution of1-ethyl-1-methyl-4-oxopiperidinium iodide (D9, 7.0 g, 26.0 mmol) inethanol (20 mL) and water (10 mL) added. After 2 h at the sametemperature the reaction was partitioned between aqueous sodiumbicarbonate and dichloromethane. Chromatography on silica (20 g),eluting with 0-10% 2M ammonia in methanol-dichloromethane, gave1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone(1.9 g, 7.05 mmol, 45.1% yield) as a straw coloured oil.

DESCRIPTION 74 1,1-Dimethylethyl4-[bis(phenylmethyl)amino]-1-piperidinecarboxylate. (D74)

1,1-Dimethylethyl 4-amino-1-piperidinecarboxylate (100 g, 499 mmol) wasdissolved in 1,2-dichloroethane (DCE) (1000 mL), 55 mL (1.1 eq) ofbenzaldehyde were added and finally 127 g (1.2 eq.) of sodiumtriacetoxyborohydride were added portionwise.

The suspension was stirred overnight, then further 55 mL (1.1 eq) ofbenzaldehyde were added and 127 g (1.2 eq.) of sodiumtriacetoxyborohydride were added portionwise and stirred for 5 h, thenfurther 28 mL (0.55 eq) of benzaldehyde were added and finally 64 g (0.6eq.) of sodium triacetoxyborohydride were added portionwise and stirredovernight.

The reaction was treated with 3 L of NaHCO₃ saturated solution until pHwas basic, resulting mixture was diluted with water (500 mL) and DCM(1.5 L). Phases were separated, the organic layer was washed with brine(2×1 L), dried over Na₂SO₄ and concentrated under vacuum. The residuewas triturated with methanol (700 mL). The suspension was filteredthrough sintered glass funnel and the solid washed with methanol (100mL). Obtained white solid was dried under vacuum to give title material(161 g; 85%).

¹H NMR δ (CDCl₃, 400 MHz): 1.47 (9H, s), 1.56 (2H, m), 1.82 (2H, m),2.72-2.50 (3H, m), 3.66 (4H, m), 4.17 (2H, bs), 7.23 (2H, m), 7.31 (4H,m), 7.38 (4H, m).

DESCRIPTION 75 N,N-bis(Phenylmethyl)-4-piperidinamine. (D75)

1,1-Dimethylethyl 4-[bis(phenylmethyl)amino]-1-piperidinecarboxylate D74(160 g, 420 mmol) was dissolved in dichloromethane (DCM) (1 L) and TFA(188 mL, 2443 mmol) was added dropwise at room temperature. Theresulting mixture was stirred for 3 h then further 100 mL of TFA wasadded and stirred for 2 h. The mixture was concentrated under reducedpressure and the residue treated with saturated solution NaHCO₃ (1.5 L)and NaOH (3M solution; 200 mL) to basic pH. The aqueous phase wasextracted with DCM (2×1.5 L). Combined organic layers were diluted withethyl acetate (100 mL), washed with water (1×1 L) and brine (1×1 L) thendried on Na₂SO₄ and concentrated to obtain title material (118 g; 100%).

¹H NMR δ (CDCl₃, 400 MHz): 1.56 (2H, qd), 1.83 (2H, m), 2.49 (2H, td),2.60 (1H, tt), 3.12 (2H, d), 3.66 (4H, s), 7.22 (2H, m), 7.30 (4H, t),7.38 (4H, d).

DESCRIPTION 761-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-N,N-bis(phenylmethyl)-4-piperidinamine.(D76)

In a 4000 mL round-bottomed flask4-{[2-(methyloxy)ethyl]oxy}cyclohexanone D61 (78.7 g, 457 mmol) wasdissolved in 1,2-dichloroethane (DCE) (2000 mL) to give a colourlesssolution. N,N-bis(phenylmethyl)-4-piperidinamine D75 (96.3 g, 343 mmol)was added, then titanium (IV) isopropoxide (174 mL, 584 mmol) was addedand the mixture was stirred at room temperature. After 22 hcyano(diethyl)aluminium 1M in toluene (650 mL, 650 mmol) was added andthe mixture was allowed to stir at room temperature for 20 h. Thereaction was quenched by dropwise addition of 1.5 L of saturated sodiumbicarbonate solution under mechanical stirring; the resulting mixturewas filtered over a Celite® pad washing the panel with 800 mL of DCM.The organic layer was dried over anhydrous sodium sulphate and finallyconcentrated to dryness to afford 151.4 g of a crude oil that wasdissolved in tetrahydrofuran (THF) (1500 mL) in a 4 L pear flask to givea colourless solution. The solution was chilled to 0° C. andmethylmagnesium bromide 3M in diethyl ether solution (601 mL, 1804 mmol)was added dropwise. The reaction was allowed to stir at roomtemperature.

The day after, the work up was performed in the following way: themixture was chilled to 0° C. and quenched by dropwise addition of 300 mLof water (strong gas evolution, salt precipitation was observed). Theresulting mixture was diluted with 1.5 L of diethyl ether. Thesuspension was filtered and the solid was washed with 2×400 mL of DCM.The two organic phases were combined and dried over anhydrous sodiumsulphate and finally concentrated under vacuum to afford 129 g of acrude white solid. The crude product was added to a silica gel column(1400 g) and was eluted with DCM/MeOH/NH₃ 2M in methanol from 2000/0/0to 2000/150/0 ending with 2000/150/30. Collected fractions wereevaporated under vacuum to givecis,trans-[1′-methyl-4-{[2-(methyloxy)ethyl]oxy}-1,1′-bi(cyclohexyl)-4-yl]bis(phenyl methyl)amine mixture (120.4 g, yield=77% consideringcis/trans mixture) as white solid. 119 g of this material were purifiedby preparative HPLC. Evaporation of collected fraction afforded titlematerial (35.6 g; 30% considering only preparative HPLC separation step)as white solid.

Preperative HPLC Conditions:

Preparative instrument: Hipersep LC110 lab unit and Novasep LC50 mm DACcolumn.

Column: Kromasil Silica 10 um 60 angstrom (50 mm×27 cm)

Mobile phase: 50% C7: 50% MTBE with 0.25% v/v DEA

Flow rate: 200 mL/min

Main Pump stroke length: 5 mm

Sample pump stroke length: 2 mm

Mixer valve: 60 mm

UV detection wavelength: 254 nm

Overall run time: 6 mins

Sample preparation: 50 g/L cis/trans mixture dissolved in DCM

Sample load: 2 g.

¹H NMR δ (CDCl₃, 400 MHz): 0.86 (3H, s), 1.44 (4H, m), 1.61 (4H, m),1.84 (4H, m), 1.97 (2H, t), 2.47 (1H, t), 3.00 (2H, d), 3.37 (1H, m),3.39 (3H, s), 3.55 (4H, m), 3.66 (4H, m), 7.20 (2H, t), 7.30 (4H, t),7.37 (4H, d).

DESCRIPTION 771-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinamine.(D77)

1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-N,Nbis(phenylmethyl)-4-piperidinamine D76 (42.5 g, 94 mmol) was dissolvedin dry methanol (425 mL). Pd/charcoal 10% w/w (16.05 g, 15.09 mmol) andammonium formate (59.5 g, 943 mmol) were added (caution, flammable;operation carried out under Argon) and the mixture heated at 80° C. for1 h. Reaction mixture was cooled down to room temperature and filtered,washing with MeOH. Volatiles were evaporated to dryness under reducedpressure to afford title compound (25.2 g, 93 mmol, yield=99%) as palegrey oil.

¹H NMR δ (DMSO-d₆, 400 MHz): 0.79 (3H, s), 1.13 (2H, m), 1.44 (8H, m),1.69 (4H, m), 2.00 (2H, dt), 2.43 (1H, m), 2.79 (2H, d), 3.25 (3H, s),3.53-3.34 (5H, m). MH⁺=271.0

DESCRIPTION 78 3-Bromo-4-[(phenylmethyl)oxy]benzonitrile. (D78)

To a solution of 3-bromo-4-hydroxybenzonitrile (60 g, 303 mmol) inacetone (600 mL) under nitrogen, potassium carbonate (62.8 g, 455 mmol)was added followed by potassium iodide (0.503 g, 3.03 mmol). To themixture benzyl chloride (49.3 mL, 424 mmol) was added dropwise and themixture was heated at 50° C. (48° C. internal temp) for 16 h. Reactionmixture was cooled down to room temperature, taken up with water (500mL)/Et₂O (1 L). Phases were separated and the aqueous phase backextracted with Et₂O (2×500 mL). Combined organics were washed withNaHCO₃ saturated solution (400 mL), then with 1M HCl solution (400 mL)and brine. Crude solution was then dried over Na₂SO₄ and evaporatedunder reduced pressure to give crude material (110 g) as brown solidthat was triturated with c-hex (500 mL) for 30 min. The solid wascollected by filtration and washed with c-hex/EtOAc 9/1 (200 mL).Evaporation of residual solvents under high vacuum afforded titlematerial (75.5 g; 261 mmol; 86%) as pale brown solid.

¹H NMR δ (CDCl₃, 400 MHz): 5.25 (2H, s), 6.99 (1H, d), 7.43 (5H, m),7.58 (1H, dd), 7.88 (1H, d).

DESCRIPTION 793-{[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-[(phenylmethyl)oxy]benzonitrile.(D79)

To a solution of1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinamineD77 (26.8 g, 99 mmol) and 3-bromo-4-[(phenylmethyl)oxy]benzonitrile D78(26 g, 90 mmol) in dry toluene (520 mL) under argon, sodiumtert-butoxide (13.01 g, 135 mmol) and BINAP (5.62 g, 9.02 mmol) wereadded at room temperature. The resulting slurry was degassed(vacuum/Argon) 3 times, then Pd₂dba₃ (4.13 g, 4.51 mmol) was added andthe mixture heated at 70° C. for 3 h. Slurry was cooled down to roomtemperature, then taken up with EtOAc (500 mL)/water (500 mL). Phaseswere separated and the aqueous one was back extracted with EtOAc (2×500mL). Combined organics were dried over Na₂SO₄ then evaporated to drynessto get crude material as brown orange oil 62 g, which was purified bySiO₂ FC eluting with DCM/MeOH 98/2 to 95/5 to get title material (42 g,88 mmol; yield 97%) as thick yellow oil.

¹H NMR δ (CDCl₃, 400 MHz): 0.94 (3H, s), 1.46 (6H, m), 1.67 (2H, m),1.86 (2H, m), 2.05 (2H, m), 2.28 (2H, m), 2.95 (2H, m), 3.26 (1H, m),3.41 (4H, bs), 3.58 (4H, m), 4.37 (1H, d), 5.13 (2H, s), 6.79 (1H, d),6.82 (1H, d), 6.94 (1H, dd), 7.40 (5H, m). MH⁺=478.17

DESCRIPTION 80 (Alternative Procedure for Preparation of D36)4-Hydroxy-3-{[1-(trans-1-methyl-4-{[2(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile.(D80)

To a solution of3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-[(phenylmethyl)oxy]benzonitrileD79 (37 g, 77 mmol) in ethyl acetate (555 mL) under a nitrogenatmosphere, palladium on carbon 10% w/w (9.25 g, 8.69 mmol) wascarefully added. The resulting slurry was hydrogenated at atmosphericpressure and room temperature for 15 h. Reaction mixture was filteredover Sterimat® under an Argon atmosphere, washing the solid with EtOAc.Solvent was evaporated under vacuum to give crude material, (33 g) asyellow foam that was purified by SiO₂ FC eluting with DCM/MeOH/NH₄OHfrom 95/5/0 to 9/1/0 to 90/10/0.5 to 90/10/1 to 85/15/2. Evaporation ofvolatiles afforded title material (26.33 g, 67.9 mmol, yield 88%) as offwhite foamy solid.

¹H NMR δ (CDCl₃, 400 MHz): 1.07 (3H, s), 1.46 (2H, m), 1.65 (4H, m),1.76 (2H, m), 1.94 (2H, m), 2.13 (2H, m), 2.43 (2H, m), 3.13 (3H, m),3.28 (3H, m), 3.42 (3H, s), 3.59 (4H, m), 6.64 (1H, d), 6.75 (1H, d),6.90 (1H, dd). MH⁺=388.14

DESCRIPTION 81 bis(1,1-Dimethylethyl)(4-methyl-2-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}phenyl)propanedioate.(D81)

Polymer supported cyanoborohydride (86 mg, 0.37 mmol, 4.3 mmol/g) wasadded to a solution of1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone(D73, 49 mg, 0.18 mmol), bis(1,1-dimethylethyl)(2-amino-4-methylphenyl)propanedioate (D39, 59 mg, 0.19 mmol) and aceticacid (0.06 mL, 1.05 mmol) in DCM (2.5 mL). The mixture was heated bymicrowave at 100° C. for 10 min before being filtered and concentratedby rotary evaporation to give bis(1,1-dimethylethyl)(4-methyl-2-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}phenyl)propanedioate(D81, 106 mg, 58%) as a colourless oil, which was used without furtherpurification.

LCMS: [M+H]⁺575

DESCRIPTION 82 2-Nitro-4-[(trifluoromethyl)sulfonyl]phenol. (D82)

Sodium hydroxide (211 mg, 5.28 mmol) was added to a suspension of1-chloro-2-nitro-4-[(trifluoromethyl)sulfonyl]benzene (297 mg, 1.03mmol) in H₂O (5 mL) at rt, followed by methanol (0.5 mL) to solubilisethe starting material, and the reaction was heated at 110° C. for 1 h.The mixture was allowed to cool to rt, diluted with H₂O (10 mL) andneutralised with 5 M HCl. DCM was added, the 2 layers were partitionedand the aqueous layer was extracted with DCM (2×). The combined organicswere dried (Na₂SO₄) and concentrated by rotary evaporation to give2-nitro-4-[(trifluoromethyl)sulfonyl]phenol (D82, 70 mg, 25%) as acolourless oil.

LCMS: [M−H]⁻ 270

DESCRIPTION 83 2-Amino-4-[(trifluoromethyl)sulfonyl]phenol. (D83)

A solution of 2-nitro-4-[(trifluoromethyl)sulfonyl]phenol (D3, 40 mg,0.13 mmol) in ethanol (2.5 mL) was reduced using an H-Cube (full H₂mode, 25° C., 1 mL/min). The reaction mixture was concentrated by rotaryevaporation to give 2-amino-4-[(trifluoromethyl)sulfonyl]phenol (D83, 35mg, 97%) as a colourless oil.

LCMS: [M−H]⁻ 240

DESCRIPTION 842-({1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)-4-[(trifluoromethyl)sulfonyl]phenol.(D84)

Polymer supported cyanoborohydride (61 mg, 0.26 mmol, 4.3 mmol/g) wasadded to a solution of 2-amino-4-[(trifluoromethyl)sulfonyl]phenol (D83,35 mg, 0.12 mmol),1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinone (D17, 35 mg,0.14 mmol) and acetic acid (0.04 mL, 0.61 mmol) in THF (2.5 mL). Themixture was heated by microwave at 100° C. for 30 min and then for afurther 1 h. A further portion of1-[trans-1-methyl-4-(propyloxy)-cyclohexyl]-4-piperidinone (D17, 10 mg)was added and the reaction was heated in the microwave for a 2 h andthen for a further 4×1 h. The reaction was then filtered andconcentrated by rotary evaporation to give a yellow oil which waspurified via flash column chromatography (silica, DCM to 0.5% NH₃/9.5%MeOH/90% DCM) to give2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)-4-[(trifluoromethyl)sulfonyl]phenol(D84, 22 mg, 36%) as a white solid.

LCMS: [M+H]⁺479

DESCRIPTION 85 3-Methyl-4-(methylsulfonyl)phenol. (D85)

A solution of mCPBA (1.97 g, 8.01 mmol, 70% wt. in H₂O) in DCM (10 mL)was added to a solution of 3-methyl-4-(methylthio)phenol (590.8 mg, 3.83mmol) in DCM (10 mL) at 0° C. under Ar. The reaction was stirred for 1 h(during which time a white precipitate formed) and then quenched withsat. NaHCO₃ (10 mL). The 2 phases were separated and the aqueous phasewas extracted with DCM (2×). The combined organics were washed with H₂Oand sat. NaCl, dried (Na₂SO₄) and concentrated by rotary evaporation togive 3-methyl-4-(methylsulfonyl)phenol (D85, 503 mg, 60%) as a yellowgum.

LCMS: [M+H]⁺ 187

DESCRIPTION 86 5-Methyl-4-(methylsulfonyl)-2-nitrophenol. (D86)

3-Methyl-4-(methylsulfonyl)phenol (D85, 503 mg, 2.29 mmol) was dissolvedin DCM (5 mL) and 70% nitric acid (0.16 mL, 3.58 mmol) was addeddropwise to the reaction. The mixture was stirred o/n. A further 2 mL of70% nitric acid was then added. The reaction was stirred for 4 h, thenH₂O (20 mL) was added and the 2 phases were separated. The aqueous layerwas extracted with DCM and the combined organics were dried (Na₂SO₄) andconcentrated by rotary evaporation to give a yellow solid, which waspurified via flash column chromatography (silica, iso-hexane to 50%EtOAc/50% iso-hexane) to give a yellow solid. This solid was trituratedwith Et₂O (2×) to give 5-methyl-4-(methylsulfonyl)-2-nitrophenol (D86,103 mg, 19%) as a yellow solid.

LCMS: [M−H]⁻ 230

DESCRIPTION 87 2-Amino-5-methyl-4-(methylsulfonyl)phenol. (D87)

5-Methyl-4-(methylsulfonyl)-2-nitrophenol (D86, 103 mg, 0.45 mmol) wasdissolved in EtOH:EtOAc (20 mL, 1:1) and was reduced using an H-Cube(full H₂ mode, 25° C., 1 mL/min). The reaction was concentrated byrotary evaporation and the crude residue was purified via flash columnchromatography (silica, DCM to 0.5% NH₃/9.5% MeOH/90% DCM) to give2-amino-5-methyl-4-(methylsulfonyl)phenol (D87, 48 mg, 41%) as a yellowsolid.

LCMS: [M+H]⁺ 202

DESCRIPTIONS 88 and 895-Methyl-2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)-4-(methylsulfonyl)phenol.(D88) and5-Methyl-4-(methylsulfonyl)-2-({1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)phenol.(D89)

Polymer supported cyanoborohydride (110 mg, 0.47 mmol, 4.3 mmol/g) wasadded to a solution of 2-amino-5-methyl-4-(methylsulfonyl)phenol (D87,48 mg, 0.24 mmol),1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinone (D17, 65 mg,0.26 mmol, this specific batch contained-25%1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinone) and acetic acid (0.07mL, 1.19 mmol) in THF (2.5 mL). The mixture was heated by microwave at100° C. for 30 min and then for a further 3×30 min. The reaction wasthen filtered and concentrated by rotary evaporation to give a yellowoil, which was purified by high pH MDAP to give5-methyl-2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)-4-(methylsulfonyl)phenol(D88, 49 mg, 46%) as a cream solid and5-methyl-4-(methylsulfonyl)-2-({1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)phenol(D89, 14 mg, 13%) as a yellow oil.

D88—LCMS: [M+H]⁺ 439

D89—LCMS: [M+H]⁺ 425

DESCRIPTION 90 5-Hydroxy-2-methylbenzonitrile. (D90)

Concentrated sulfuric acid (5 mL, 94 mmol) was added to H₂O (10 mL)(causing an exotherm). While the diluted acid was still hot,5-amino-2-methylbenzonitrile (826 mg, 6.25 mmol) was added giving aclear solution. This was cooled to 15° C. (during which time aprecipitate occurred) and 8 g of ice was added. As soon as thetemperature was below 5° C., a solution of sodium nitrite (522 mg, 7.57mmol) in H₂O (5 mL) was added from a syringe (with the needle extendedbelow the surface of the liquid) keeping the internal temperature below5° C. The solution went clear after 5 min of stirring and then cold H₂O(5 mL), urea (59 mg, 0.97 mmol) and ice (5 g) were added sequentially.In a separate flask H₂O (5 mL) was added to sodium sulfate (4.75 g, 33.4mmol) under an atmosphere of argon. Concentrated sulfuric acid (10 mL)was cautiously added and the reaction heated to reflux. The diazoniumspecies was added to the refluxing mixture in portions and the heatingcontinued for 2 h (NOTE: Blast shield used during heating). The mixturewas cooled to rt and extracted with Et₂O (2×). The combined organicswere washed with H₂O and 10% Na₂CO₃ solution before being extracted with10% NaOH solution. The NaOH solution was acidified with concentrated HCland then extracted with Et₂O (2×). The combined organics from thissecond extraction were dried (Na₂SO₄) and concentrated by rotaryevaporation to give a light brown solid which was purified via flashcolumn chromatography (silica, DCM to 0.5% NH₃/9.5% MeOH/90% DCM) togive 5-hydroxy-2-methylbenzonitrile (D90, 476 mg, 52%) as an orangesolid.

LCMS: [M−H]⁻ 132

DESCRIPTION 91 5-Hydroxy-2-methyl-4-nitrobenzonitrile. (D91)

5-Hydroxy-2-methylbenzonitrile (D90, 475 mg, 3.57 mmol) was dissolved inDCM (5 mL) and 70% nitric acid (1 mL, 22 mmol) was added dropwise to thereaction. The mixture was stirred for 45 min before the addition of H₂O(15 mL). The two phases were separated and the aqueous phase wasextracted with DCM (2×). The combined organics were dried (Na₂SO₄) andconcentrated by rotary evaporation to give a yellow solid. The cruderesidues were purified by flash column chromatography (silica, 10%EtOAc/90% iso-hexane to 50% EtOAc/50% iso-hexane) to give5-hydroxy-2-methyl-4-nitrobenzonitrile (D91, 186 mg, 26%) as a yellowsolid.

LCMS: [M−H]⁻ 177

DESCRIPTION 92 4-Amino-5-hydroxy-2-methylbenzonitrile. (D92)

5-hydroxy-2-methyl-4-nitrobenzonitrile (D91, 185 mg, 1.04 mmol) wasdissolved in EtOH:EtOAc (24 mL, 1:1) and was reduced using an H-Cube(full H₂ mode, 25° C., 1 mL/min). The reaction was concentrated byrotary evaporation to give 4-amino-5-hydroxy-2-methylbenzonitrile (D92,152 mg, 95%) as a pale yellow solid.

LCMS: [M+H]⁺149

DESCRIPTION 935-Hydroxy-2-methyl-4-[1-(trans-1-methyl-4-{[2-(methyloxy)-ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile.(D93)

Polymer supported cyanoborohydride (199 mg, 0.86 mmol, 4.3 mmol/g) wasadded to a solution of 4-amino-5-hydroxy-2-methylbenzonitrile (D92, 65mg, 0.44 mmol),1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone(D73, 117 mg, 0.43 mmol) and acetic acid (0.12 mL, 2.17 mmol) in THF(2.5 mL). The mixture was heated by microwave at 100° C. for 1 h andthen for a further 2 h. An extra 50 mg of polymer supportedcyanoborohydride was added and the reaction heated by microwave at 100°C. for 2×1 h. The reaction was then filtered and concentrated by rotaryevaporation to give a yellow oil, which was purified via high pH MDAP togive5-hydroxy-2-methyl-4-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile(D93, 62 mg, 36%) as a green oil.

LCMS: [M+H]⁺402

DESCRIPTION 94 4-(Difluoromethoxy)-2-nitrophenol. (D94)

4-(Difluoromethoxy)phenol (500 mg, 3.12 mmol) was dissolved in DCE (3mL). The reaction mixture was cooled to 0° C. and nitric acid (0.488 mL,10.92 mmol) was added dropwise over 10 min. The reaction mixture wasstirred for a further hour at 0° C., then poured into an ice/water mix(5 g in 5 mL). DCE (10 mL) was added and the layers separated. Theorganic layer was dried (MgSO₄) and evaporated to dryness to give acrude brown oil (550 mg). Material was carried forward without furtherpurification, as no separation between products was found in TLC solventsystems used. (M−H)⁻=204.

¹H NMR δ (CDCl₃): 6.51 (1H, t, J=71.2 Hz), 7.18 (1H, d, J=7.2 Hz), 7.3(1H, dd, J=9.2, 2.8 Hz), 7.91 (1H, s), 10.45 (1H, s).

DESCRIPTION 95 4-(Difluoromethoxy)-2-aminophenol. (D95)

A mixture of 4-(difluoromethoxy)-2-nitrophenol (D94, 450 mg, 1.974mmol), Raney-nickel (est. 200 mg), 1,4-dioxane (10 mL) and water (5 mL)was stirred at room temperature in a hydrogen atmosphere for 20 h. Thereaction mixture was filtered through kieselguhr under an argonatmosphere and evaporated to dryness. The unreacted starting materialwas sufficiently volatile that most of it was removed by using a rotaryevaporator. The residue was purified by flash column chromatography on apre-packed silica cartridge (column size 50 g), eluting with 0-30% ethylacetate in hexane, followed by 10-50% 2 M ammonia in methanol in DCM.The residue was further purified on an IST SCX-2 cartridge 20 g, washingwith methanol (125 mL) and eluting with 2 M ammonia in methanol (125mL). The basic eluent was evaporated to dryness to afford the desiredproduct (D95) as a brown solid (200 mg). (M+H)⁺=176.

¹H NMR δ (CDCl₃): 6.38 (1H, t, J=74.6 Hz), 6.41 (1H, dd, J=8.6 Hz, 2.6Hz), 6.55 (1H, d, J=8.0 Hz), 6.67 (1H, d, J=8.4 Hz).

DESCRIPTION 964-(Difluoromethoxy)-2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)phenol.(D96)

1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8, 114 mg,0.476 mmol) was dissolved in DCM (2.5 mL) and acetic acid (0.25 mL) and2-amino-4-(difluoromethoxy)phenol (D95, 100 mg, 0.572 mmol) was added,followed by macroporous triethylammonium methylpolystyrenecyanoborohydride (412 mg, 0.953 mmol). The reaction mixture was heatedin a microwave reactor at 100° C. for 10 min. The reaction mixture wasfiltered and evaporated to dryness. The crude product was purified byflash column chromatography on a pre-packed silica cartridge (columnsize 10 g), eluting with 0-10% 0.2 M ammonia in methanol in DCM toafford the desired compound D96 as a pale brown oil (118 mg).(M+H)⁺=399.

DESCRIPTION 974-Methyl-2-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}phenol.(D97)

1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone(D73, 60 mg, 0.223 mmol) was dissolved in DCM (1.25 mL) and acetic acid(0.125 mL) and 2-amino-4-methylphenol (32.9 mg, 0.267 mmol) was added,followed by macroporous triethylammonium methylpolystyrenecyanoborohydride (193 mg, 0.445 mmol). The reaction mixture was heatedin a microwave reactor at 100° C. for 10 min. The reaction mixture wasfiltered and evaporated to dryness. The crude product was purified byflash column chromatography on a pre-packed silica cartridge (columnsize 10 g), eluting with 5-10% 0.2 M ammonia in methanol in DCM toafford the desired compound as a colourless oil (56 mg). (M+H)⁺=377.

DESCRIPTION 982-{[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-(methyloxy)phenol.(D98)

1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone(D73, 55 mg, 0.204 mmol) was dissolved in DCM (1.25 mL) and acetic acid(0.125 mL) and 2-amino-4-methoxyphenol (37 mg, 0.266 mmol) was added,followed by macroporous triethylammonium methylpolystyrenecyanoborohydride (177 mg, 0.408 mmol). The reaction mixture was heatedin a microwave reactor at 100° C. for 10 min. The reaction mixture wasfiltered and evaporated to dryness. The crude product was purified byflash column chromatography on a pre-packed silica cartridge (columnsize 10 g), eluting with 5-10% 0.2 M ammonia in methanol in DCM toafford the desired compound as a yellow oil (12 mg). Due to the poorrecovery, the remaining fractions were combined and evaporated to give ayellow oil (20 mg). The yellow oils were combined to give the desiredproduct as a crude yellow oil (31 mg). The material was carried forwardwithout further purification.

¹H NMR δ (CDCl₃): 1.26 (3H, s), 1.40 (3H, br. m), 1.88 (6H, br. m), 2.04(4H, m), 2.24 (2H, br. m), 2.83 (2H, br.m), 3.30 (2H, br. m), 3.38 (3H,s), 3.42 (3H, br. m), 3.53 (2H, m), 3.60 (2H, m), 3.72 (2H, br. m), 6.18(1H, m), 6.72 (1H, m).

DESCRIPTION 99 Ethyl 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylate.(D99)

Triethylsilane (10 mL, 63 mmol) was added to a solution of ethyl4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D1,13.6 g, 47.4 mmol), bismuth tribromide (923 mg, 2.06 mmol) andcyclopropanecarbaldehyde (4.25 mL, 56.8 mmol) in acetonitrile (60 mL) atrt under Ar. A black precipitate and an exotherm occurred on theaddition of the triethylsilane. The mixture was stirred for 1 h beforebeing poured on to sat. NaHCO₃ (200 mL). The reaction was extracted withEtOAc (2×) and the combined organics were washed (sat. NaCl), dried(Na₂SO₄) and concentrated by rotary evaporation to give a mixture of cisand trans ethyl 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylate (D99,20.8 g, 97%, contained silyl residues) as a colourless oil.

¹H NMR δ (CDCl₃, 400 MHz) mixture of approx. 1:1 cis:trans 0.15-0.20(2H, m), 0.47-0.54 (2H, m), 1.02 (1H, m), 1.20-1.28 (3H, m), 1.39-2.10(8H, m), 2.23 (0.5H, m), 2.34 (0.5H, m), 3.17-3.30 (2.5H, m), 3.45(0.5H, m), 4.06-4.15 (2H, m).

DESCRIPTION 100 4-[(Cyclopropylmethyl)oxy]cyclohexanecarboxylic acid.(D100)

Ethyl 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylate (D99, 20.8 g,45.8 mmol) was taken up in THF (50 mL)/methanol (50 mL). Sodiumhydroxide (20 mL, 250 mmol, concentrated) was added to the solutionwhich was left to stir o/n. The THF/methanol was evaporated and thecrude residue washed with Et₂O. The aqueous layer was acidified with 5 MHCl and extracted with EtOAc (2×). The EtOAc organics were combined,dried (Na₂SO₄) and the solvent evaporated to give a mixture of cis andtrans 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylic acid (D100, 9.47g, 94%) as a yellow oil.

¹H NMR δ (CDCl₃, 400 MHz) mixture of approx. 1:1 cis:trans 0.12-0.19(2H, m), 0.45-0.53 (2H, m), 0.95-1.06 (1H, m), 1.19-1.32 (1H, m),1.38-1.69 (3.5H, m), 1.72-1.83 (1H, m), 1.84-2.10 (2.5H, m), 2.27 (0.5H,m), 2.38 (0.5H, m), 3.17-3.29 (2.5H, m), 3.44 (0.5H, m), 10.85 (1H, br.s).

DESCRIPTION 101 4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylicacid—mixture of cis and trans. (D101)

Diisopropylamine (15 mL, 105 mmol) in THF (100 mL) was cooled to 0° C.under Ar. n-Butyllithium (38 mL, 95 mmol, 2.5M in hexane) was addeddropwise over 10 min. The reaction mixture was left to stir for 15 minat 0° C. A solution of 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylicacid (D100, 9.47 g, 43.0 mmol) in THF (50 mL) was added and theresulting yellow solution was heated at 50° C. for 2 h. The reactionmixture was cooled to 0° C. and iodomethane (8 mL, 128 mmol) was addeddropwise, the reaction was then allowed to warm to rt and left to stirfor 3 days. 10% Citric acid (200 mL) was then added and the reactionmixture was concentrated by rotary evaporation. The residual mixture wasdiluted with H₂O and extracted with Et₂O (2×). The organics werecombined, dried (Na₂SO₄) and concentrated by rotary evaporation to givea mixture of cis and trans4-[(cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylic acid (D101,10.0 g, 93%) as a brown oil.

¹H NMR δ (DMSO-d₆, 400 MHz) mixture of approx. 1:1 cis:trans 0.09-0.17(2H, m), 0.39-0.47 (2H, m), 0.83-2.03 (12H, m), 3.16-3.24 (2H, m), 3.33(0.5H, m), 3.60 (0.5H, m), 12.12 (1H, br. s).

DESCRIPTION 102trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylic

4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylic acid—mixture ofcis and trans (D101, 10.0 g, 40.0 mmol) was azeotroped with PhMe (2×) toremove any trace H₂O and then dissolved in toluene (50 mL). Thionylchloride (50 mL, 685 mmol) was added and the reaction heated at 90° C.for 4 h. Excess thionyl chloride was removed by rotary evaporation andthe residue was azeotroped with toluene to remove the final traces. THF(50 mL) was added and the solution poured on to 5% Na₂CO₃ solution (200mL). The mixture was stirred vigorously for 20 min before being washedwith Et₂O (2×). The aqueous layer was then acidified with concentratedHCl and extracted with EtOAc (2×). The combined EtOAc organics weredried (Na₂SO₄) and concentrated by rotary evaporation to give a brownoil. This residue was purified by being divided into 4 roughly equalportions, each of which was purified via flash column chromatography(silica, 5% EtOAc/95% iso-hexane to 25% EtOAc/75% iso-hexane). Thedesired fractions were combined to givetrans-4-[(cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylic acid(D102, 893 mg, 10%) as a colourless oil.

¹H NMR δ (CDCl₃, 400 MHz) 0.16-0.23 (2H, m), 0.49-0.56 (2H, m), 1.05(1H, m), 1.25 (3H, s), 1.60-1.87 (8H, m), 3.26 (2H, d, J 6.8), 3.40 (1H,m).

DESCRIPTION 103trans-4-[(Cyclopropylmethyl)oxy]-1-isocyanato-1-methylcyclo-hexane.(D103)

trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylic acid(D102, 890 mg, 4.19 mmol) was dissolved in toluene (25 mL) andtriethylamine (0.760 mL, 5.45 mmol) was added, followed by diphenylphosphoryl azide (0.903 mL, 4.19 mmol). The reaction mixture was heatedat 85° C. for 2 h, then allowed to cool to room temperature overnight.The reaction mixture was treated with 1 M aq. sodium hydroxide (75 mL),then extracted with diethyl ether (3×50 mL). The combined organics weredried (MgSO₄) and evaporated to afford the desired product (D103) as acolourless oil (934 mg).

¹H NMR δ (CDCl₃): 0.18 (2H, m), 0.52 (2H, m), 1.03 (1H, m), 1.37 (3H,s), 1.54 (2H, m), 1.74 (6H, m), 3.23 (2H, d, J=6.8 Hz), 3.53 (1H, br.s).

DESCRIPTION 104 trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexanaminehydrochloride. (D104)

trans-4-[(Cyclopropylmethyl)oxy]-1-isocyanato-1-methylcyclohexane (D103,877 mg, 4.19 mmol) was dissolved THF (25 mL) and 5 M hydrochloric acid(0.127 mL, 4.19 mmol) was added. The reaction mixture was stirred atroom temperature for 3 h in an argon atmosphere. The reaction mixturewas evaporated to dryness, redissolved in THF and evaporated. This wasrepeated until a white solid was obtained. This solid was trituratedwith ethanol and dried in a vacuum oven to afford the desired product(D104, 700 mg, 76% yield).

¹H NMR δ (CD₃OD): 0.20 (2H, m), 0.51 (2H, m), 1.01 (1H, m), 1.37 (3H,s), 1.59 (4H, m), 1.87 (4H, m), 1.32 (2H, d, J=5.2 Hz), 3.42 (1H, m).

DESCRIPTION 1051-{trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexyl}-4-piperidinone.(D105)

To a solution oftrans-4-[(cyclopropylmethyl)oxy]-1-methylcyclohexanamine hydrochloride(D104, 700 mg, 3.19 mmol) in ethanol (20 mL) was added a solution ofpotassium carbonate (572 mg, 4.14 mmol) in water (10 mL), followed by1-ethyl-1-methyl-4-oxopiperidinium iodide (D9, 1500 mg, 5.57 mmol). Thereaction mixture was heated at 80° C. for 3 h. The reaction mixture wasevaporated to dryness and partitioned between DCM and saturated sodiumbicarbonate (25 mL of each). The aqueous layer was extracted withfurther DCM (2×25 mL). The combined organics were dried (MgSO₄) andevaporated to give an orange oil. The crude product was purified byflash column chromatography on a Biotage SP4 (column size 24+S), elutingwith 0-10% methanol in DCM to afford the product (D105) as an orange oil(340 mg).

¹H NMR δ (CDCl₃): 0.20 (2H, m), 0.53 (2H, m), 0.94 (3H, s), 1.05 (1H,m), 1.48-1.61 (4H, m), 1.69 (2H, m), 1.86 (2H, m), 2.41 (4H, t, J=6 Hz),2.82 (4H, t, J=6 Hz), 3.27 (2H, d, J=6.4 Hz), 3.44 (1H, m).

DESCRIPTION 1062-[(1-{trans-1-Methyl-4-[(2-methylbutyl)oxy]cyclohexyl}-4-piperidinyl)amino]-4-(methylsulfonyl)phenol.(D106)

1-{trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexyl}-4-piperidinone(D105, 170 mg, 0.641 mmol) was dissolved in THF (5 mL) and2-amino-4-(methylsulfonyl)phenol (120 mg, 0.641 mmol) was added,followed by acetic acid (0.158 mL, 2.75 mmol) and macroporoustriethylammonium methylpolystyrene cyanoborohydride (555 mg, 1.281mmol). The reaction mixture was heated in a microwave reactor at 100° C.for 90 minutes. The reaction filtered, washing with methanol to dissolvea precipitate which formed. The collected solution was evaporated togive an orange oil-solid mixture. This was triturated with THF to givethe desired product (D106) as a white solid (85 mg). (M+H)⁺=437.

DESCRIPTION 107 Phenylmethyl 1-methyl-4-oxocyclohexanecarboxylate.(D107)

2-(Trimethylsilyloxybutadiene (6.46 g, 45.4 mmol), phenylmethyl2-methyl-2-propenoate (8.00 g, 45.4 mmol), and4,4′-methanediylbis[2,6-bis(1,1-dimethylethyl)phenol] (0.019 g, 0.045mmol) were combined together in a 20.0 mL microwave vessel and heated to200° C. for 300 mins. Sample recovered and removed from vessel using THF(˜3×10 mL). The solvent was removed under reduced pressure and theresidual oil taken up in 10% 2N HCl/THF (100 mL) and stirred overnight.After this time a clear solution formed, which was diluted with water(50 mL), partitioned into DCM (2×100 mL) and the organic layersseparated, dried over MgSO₄, filtered and the solvent removed underreduced pressure. The residue was purified by FC over Silica (150 g:5-10% EtOAc/iso-hex) to afford a clear oil. Confirmed by NMR to bephenylmethyl 1-methyl-4-oxocyclohexanecarboxylate (3.48 g, 11.30 mmol,24.89% yield).

¹H NMR δ (CDCl₃, 400 MHz): 1.32 (3H, s), 1.64-1.69 (2H, m), 1.71-1.85(6H, m), 5.19 (2H, s), 7.32-7.39 (5H, m).

DESCRIPTION 108 Phenylmethyl1-methyl-4-[(1-methylethyl)oxy]-cyclohexanecarboxylate. (D108)

Neat triethylsilane (1.518 g, 13.06 mmol) was added to a stirred, cooled(0° C.) solution of phenylmethyl 1-methyl-4-oxocyclohexanecarboxylate(D107) (2.68 g, 10.88 mmol), trimethyl[(1-methylethyl)oxy]silane (1.439g, 10.88 mmol) and iron (III) chloride (0.176 g, 1.088 mmol) inacetonitrile (100 mL). The solution was stirred for 1 hour at 0° C. TLC(SiO₂ 10% EtOAc/is-hex) showed the presence of two close runningproducts, less polar than starting material and little else but somebaseline impurity. The reaction was diluted with water (100 mL),extracted into DCM (2×50 mL), the organic layers dried, filtered and thesolvent removed under reduced pressure to afford a yellow oil.Chromatography (SiO₂ 10-20% EtOAc/is-hex) afforded, phenylmethyl1-methyl-4-[(1-methylethyl)oxy]-cyclohexanecarboxylate (2.3 g, 7.92mmol, 72.8% yield) as a clear oil. NMR shows the product to be atrans:cis mix, approx 2:1.

Where possible trans and cis NMR data are identified

¹H NMR δ (CDCl₃, 400 MHz): 1.12 (6H, d, J=4.0 Hz), 1.21 (3H, s), 1.5-1.7(6H, m), 1.75-1.9 (2H, m), 3.2-3.3 (1H, m cis), 3.35-3.45 (1H m trans),3.6-3.7 (1H, sept J=4.0 Hz), 5.1 (2H, s), 7.4-7.3 (5H, m)

DESCRIPTION 109 1-Methyl-4-[(1-methylethyl)oxy]cyclohexanecarboxylicacid. (D109)

Phenylmethyl 1-methyl-4-[(1-methylethyl)oxy]cyclohexanecarboxylate(D108) (2.3 g, 7.92 mmol) was suspended in water (30 mL) andtetrahydrofuran (THF) (10 mL) along with lithium hydroxide (0.759 g,31.7 mmol). The resulting solution was warmed to reflux overnight, TLC(SiO₂ 10% EtOAc/is-hex) showed some of more polar SM present but none ofless polar SM. Reaction cooled and extracted with ether (2×20 mL) toremove unhydrolysed SM. Aqueous layer acidified with 2 N HCl (acid to pHstick) and extracted into DCM (2×15 mL). DCM layers combined and driedover MgSO₄, filtered and solvent removed under reduced pressure. NMRconfirmed 1-methyl-4-[(1-methylethyl)oxy]cyclohexanecarboxylic acid(1.13 g, 5.64 mmol, 71.2% yield) as a mixture of cis and trans isomers.As suspected from the TLC one of the isomers, suspected to be the trans(ether:carboxylate) had hydrolysed faster. This resulted in a ˜2:1 ratioof the acids.

Where possible trans and cis NMR data are identified

¹H NMR δ (CDCl₃, 400 MHz): 1.14 (6H, d, J=4.0 Hz), 1.20 (3H, s), 1.5-1.7(6H, m), 1.80-1.9 (2H, m), 3.3-3.4 (1H, m cis), 3.4-3.5 (1H m trans),3.6-3.7 (1H, sept J=4.0 Hz), 9.5-10.0 (1H, s).

DESCRIPTION 110trans-1-Methyl-4-[(1-methylethyl)oxy]cyclohexanecarboxylic acid. (D110)

1-Methyl-4-[(1-methylethyl)oxy]cyclohexanecarboxylic acid (D109) (1.13g, 5.64 mmol) was dissolved in neat thionyl chloride (2.059 mL, 28.2mmol) and warmed to reflux for three hours. The mixture was then allowedto cool to room temp and the thionyl chloride removed under reducedpressure. All thionyl chloride residue was removed by repeatedazeotropic evaporation from toluene. The residue was taken up in THF (20mL) and treated with 5% aq sodium carbonate (10 mL) for 1 hour. Thereaction was then diluted with water (20 mL), extracted with ether (2×10mL), the aqueous layer separated, acidified with 2N HCl, (pH stick) andextracted with DCM (2×10 mL). The DCM layers were combined and driedover MgSO₄, filtered and the solvent removed under reduced pressure toafford trans-1-methyl-4-[(1-methylethyl)oxy]cyclohexanecarboxylic acid(556 mg, 2.78 mmol, 49.2% yield). NMR show clean isolation of the transacid.

¹H NMR δ (CDCl₃, 400 MHz): 1.14 (6H, d, J=4.0 Hz), 1.20 (3H, s), 1.5-1.7(6H, m), 1.80-1.9 (2H, m), 3.4 (1H m), 3.64 (1H, sept J=4.0 Hz),9.5-10.0 (1H, s).

DESCRIPTION 111 trans 1-Methyl-4-(2-methoxyethoxy)cyclohexylaminehydrochloride. (D111)

A solution of trans-1-methyl-4-[(1-methylethyl)oxy]cyclohexanecarboxylicacid (D110) (556 mg, 2.78 mmol), diphenyl azidophosphate (764 mg, 2.78mmol), and triethylamine (0.387 mL, 2.78 mmol) in toluene (10 mL) waswarmed to reflux for 2 hr. The solution was then cooled to room temp,and treated with 1 N NaOH (aq, 10 mL) for three hours. After this timeether (50 mL) was added, the organic layers separated, dried over MgSO₄,filtered and the solvent removed under reduced pressure to give a clearoil. NMR is consistent with the intermediate isocyanate. The recoveredmaterial was taken up in tetrahydrofuran (THF) (10.00 mL) and treatedwith hydrochloric acid 5N (0.084 mL, 2.78 mmol) and stirred at roomtemperature for 48 hr. The solvent was removed under reduced pressureand the residue triturated from ether to affordtrans-1-methyl-4-[(1-methylethyl)oxy]-cyclohexanamine (335 mg, 1.956mmol, 70.5% yield). NMR is consistent with the structure of the desiredproduct.

¹H NMR δ (d₄-MeOH, 400 MHz): 1.14 (6H, d, J=4.0 Hz), 1.4 (3H, s),1.5-1.6 (6H, m), 1.6-1.7 (2H, m), 3.5 (1H m), 3.74 (1H, sept J=4.0 Hz).

DESCRIPTION 1121-{trans-1-Methyl-4-[(1-methylethyl)oxy]cyclohexyl}-4-piperidinone

1-Ethyl-1-methyl-4-oxopiperidinium iodide (D9; 354 mg, 1.315 mmol) wasadded to a stirred solution oftrans-1-methyl-4-[(1-methylethyl)oxy]cyclohexylamine hydrochloride(D111) (227 mg, 1.315 mmol) and potassium carbonate (132 mg, 0.955 mmol)in ethanol (14 mL)/water (7 mL) and the resulting solution warmed toreflux for three hours. The mixture was then allowed to cool to roomtemp and partitioned into NaHCO₃ solution (aq sat. 25 mL) and extractedinto DCM (3×20 mL). The combined extracts were dried over MgSO₄,filtered and the solvent removed under reduced pressure to afford ayellow oil. Purification by FC, SiO₂ (3-5% 2N NH₃/MeOH/DCM) afforded1-{trans-1-methyl-4-[(1-methylethyl)oxy]cyclohexyl}-4-piperidinone (140mg, 0.553 mmol, 42.0% yield). NMR consistent with desired product.

¹H NMR δ (CDCl₃, 400 MHz): 0.9 (3H, s), 1.12 (6H, d, J=4.0 Hz), 1.4-1.5(2H, m), 1.5-1.6 (2H, m), 1.6-1.7 (2H, m), 1.7-1.8 (2 h, m), 2.4 (4H, tJ=8.0 Hz), 2.85 4H, t J=8.0 Hz) 3.45 (1H m), 3.65 (1H, sept J=4.0 Hz).

DESCRIPTION 1132-[(1-{trans-1-Methyl-4-[(1-methylethyl)oxy]cyclohexyl}-4-piperidinyl)amino]-4-(methylsulfonyl)phenol.(D113)

1-{trans-1-Methyl-4-[(1-methylethyl)oxy]cyclohexyl}-4-piperidinone(D112, 140 mg, 0.553 mmol) was dissolved in THF (5 mL) and2-amino-4-(methylsulfonyl)phenol (103 mg, 0.550 mmol) was added,followed by acetic acid (0.135 mL, 2.366 mmol) and macroporoustriethylammonium methylpolystyrene cyanoborohydride (595 mg, 1.375mmol). The reaction mixture was heated in a microwave reactor at 100° C.for 60 minutes. The reaction mixture was scratched, causing aprecipitate to form. The reaction mixture was filtered. Methanol wasadded to the collected solid to dissolve the precipitate, leaving behindthe insoluble resin. The methanol solution was evaporated to give thedesired product as a tan solid (125 mg).

¹H NMR δ (CD₃OD): 1.14 (6H, d, J=6.0 Hz), 1.38 (3H, s), 1.45 (2H, m),1.73 (4H, m), 2.02 (4H, m), 2.30 (2H, m), 3.05 (3H, s), 3.12 (2H, m),3.34 (2H, s), 3.39 (1H, m), 3.57 (2H, m), 3.67 (2H, m), 3.77 (1H,septet, J=6.2 Hz), 6.83 (1H, d, J=8.0 Hz), 7.10 (1H, s), 7.13 (1H, d,J=8.0 Hz).

DESCRIPTION 1142-{[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-(trifluoromethyl)phenol.(D114)

2-Amino-4-(trifluoromethyl)phenol (65.8 mg, 0.371 mmol),1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone(D73) (100 mg, 0.371 mmol), PS-CNBH₃ (354 mg, 0.817 mmol) were placed ina 5 mL microwave tube, AcOH (0.13 mL, 2.271 mmol) and dichloromethane(DCM) (2.5 mL) were added. The tube was sealed and heated to 100° C. for15 min, fixed hold time. The reaction mixture was filtered and thefiltrate evaporated to give a clear oil. The oil was purified on a 10 gsilica column, eluent —NH3/MeOH/DCM. This gave a clear oil2-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-(trifluoromethyl)phenol(109 mg, 0.253 mmol, 68.2% yield).

¹H NMR δ (CDCl₃, 400 MHz) 0.9 (3H,$), 1.4-1.6 (6H, br m), 1.7 (3H, brm), 1.9 (2H, br m), 2.1 (2H, br m), 2.35 (2H, t, J=12.0 Hz), 3.05 (2H,d, J=12.0 Hz), 3.25 (2H, br m), 3.4 (3H, s), 3.55 (4H, m), 4.5 (1H, brs), 6.70 (1H, d, J=8.0 Hz), 6.76 (1H, s), 6.82 (1H, d, J=8.0 Hz).

DESCRIPTION 115 2-Fluoro-4-methyl-6-nitrophenol. (D115) (Scale-upPreparation of D41)

2-Fluoro-4-methylphenol (2.6 g, 20.61 mmol) was dissolved indichloromethane (DCM) and placed in a 100 mL RB flask. Nitric acid, 70%(1.576 mL, 24.74 mmol) was added dropwise (exotherm observed). Thereaction mixture was left to stir for ˜1 hr, washed with water, theorganic dried and evaporated to give a yellow solid,2-fluoro-4-methyl-6-nitrophenol (3.276 g, 19.14 mmol, 93% yield).

¹H NMR δ (CDCl₃, 400 MHz) 2.35 (3H,$), 7.26 (1H, d, J=1.0 Hz), 7.71 (1H,d, J=1.0 Hz), 10.3 (1H, s).

DESCRIPTION 116 2-Fluoro-4-methyl-6-aminophenol. (D116) (Scale-UpPreparation of D42)

2-Fluoro-4-methyl-6-nitrophenol (D115, 3.276 g, 19.14 mmol) wasdissolved in ethanol (100 mL). 10% Pd/C (0.323 g, 0.304 mmol) was addedand the reaction mixture hydrogenated for ˜18 hr. Catalyst was filteredoff and the filtrate evaporated to dryness. TLC showed only a smallamount of material had been reduced. Solid was redissolved in 350 mLethanol, 150 mL of this solution was passed down the H-cube at 1 mL/minwith full hydrogen. After ˜2 hr the cartridge had been exhausted. A newcartridge was used and the reaction mixture was left recycling throughthe instrument for ˜4 hr. ˜30% of nitro compound was still remaining.The reaction mixture was evaporated to dryness.

Redissolved in EtOH and passed through the H-cube with a new cartridgeto give fully reduced material 2-fluoro-4-methyl-6-aminophenol (907 mg,6.43 mmol, 33.6% yield) as a brown solid. The remaining nitro compoundwas passed down the H-cube at 1 mL/min with full hydrogen—still only 58%conversion. Redissolved in EtOH and passed through the H-cube with a newcartridge. Evaporated to dryness redissolved in MeOH and loaded onto anSCX-2 cartridge (50 g) washed with MeOH and eluted with 1M NH₃/MeOH,evaporated to dryness to give a brown solid batch 2 (1.319 g, 9.35 mmol,48.8% yield).

¹H NMR δ (CDCl₃, 400 MHz) 2.18 (3H,$), 3.5 (2H, br s), 6.33 (2H, br m),7.47 (1H, s).

DESCRIPTION 117[4-({[4-(Methyloxy)phenyl]methyl}oxy)-3-nitrophenyl]methanol. (D117)

To a solution of 4-(hydroxymethyl)-2-nitrophenol (2.20 g, 13.01 mmol) inDMF (60 mL) was added cesium carbonate (8.48 g, 26.0 mmol) followed bythe portionwise addition of 4-methoxybenzyl chloride (3.06 g, 19.51mmol). After stirring at rt for 45 mins additional 4-methoxybenzylchloride (2.037 g, 13.01 mmol) was added followed by tetrabutylammoniumiodide (2.402 g, 6.50 mmol). The reaction mixture was stirred at rt for18 hr and then diluted with EtOAc (200 mL) and washed successively withwater, 10% aq. K₂CO₃, water and finally brine, dried (MgSO₄), filteredand concentrated to dryness in vacuo. The residue was purified by silicagel chromatography eluting with 10-50% EtOAc in isohexane to afford thetitle compound as a cream solid, 2.17 g, 57.7%.

¹H NMR δ (CDCl₃): 1.81 (1H, t, J=5.6 Hz), 3.81 (3H, s), 4.67 (2H, d),5.15 (2H, s), 6.90 (2H, d), 7.10 (1H, d), 7.37 (2H, d), 7.50 (1H, m),7.85 (1H, d).

DESCRIPTION 1184-[(Methyloxy)methyl]-1-({[4-(methyloxy)phenyl]methyl}oxy)-2-nitrobenzene.(D118)

To a solution of[4-({[4-(methyloxy)phenyl]methyl}oxy)-3-nitrophenyl]methanol D117 (2.16g, 7.47 mmol) in THF (100 mL) was added iodomethane (0.700 mL, 11.20mmol) followed by the portionwise addition of a 0.5M solution ofpotassium hexamethyldisilazide (22.40 mL, 11.20 mmol) in toluene. Afterstirring at rt for 2 hr the mixture was diluted with EtOAc (150 mL) andwashed with water (2×50 mL) and brine (2×50 mL). The organic phase wasdried (MgSO₄) filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography eluting with 10-40% EtOAc inisohexane to afford the title compound as a pale orange oil whichsolidified on standing, 1.57 g, 69.3%.

¹H NMR δ (CDCl₃): 3.39 (3H, s), 3.81 (3H, s), 4.41 (2H, s), 5.16 (2H,s), 6.92 (2H, d), 7.10 (1H, d, J=8.0 Hz), 7.38 (2H, d), 7.45 (1H, m),7.82 (1H, d).

DESCRIPTION 119 2-Methyl-4-[(methyloxy)methyl]phenol. (D119)

To a solution of4-[(methyloxy)methyl]-1-({[4-(methyloxy)phenyl]methyl}oxy)-2-nitrobenzeneD118 (1.57 g, 5.18 mmol) in DCM (80 mL) was added trifluoroacetic acid(3.99 mL, 51.80 mmol). After 1 hr the mixture was washed with water(3×25 mL) and then extracted with 10% aq potassium carbonate solution(3×20 mL). The combined extracts were back washed with diethyl ether (20mL) and then the pH was adjusted to 1 with 2N HCl, the mixture wasextracted with DCM (3×25 mL), the combined extracts were washed withwater (25 mL) and brine (25 mL), dried(MgSO₄), filtered and concentratedin vacuo. The residue was purified by silica gel chromatography elutingwith 5-40% EtOAc in isohexane to afford the title compound as a brightyellow oil. 0.72 g, 76%

¹H NMR δ (CDCl₃): 3.41 (3H, s), 4.42 (2H, d), 7.15 (1H, d, J=8.4 Hz),7.56 (1H, m), 8.08 (1H, d).

DESCRIPTION 120 2-Amino-4-[(methyloxy)methyl]phenol. (D120)

A mixture of 4-[(methyloxy)methyl]-2-nitrophenol D119 (0.72 g, 3.93mmol) and platinum (IV) oxide (0.089 g, 0.393 mmol) in ethanol (15 mL)was stirred under an atmosphere of hydrogen for 16 hr. The catalyst wasremoved by filtration through celite and the filtrate concentrated todryness in vacuo to afford the title compound as a green/brown solid0.51 g, 85%.

¹H NMR δ (CDCl₃): 3.35 (3H, s), 3.7-4.5 (2H, br s+2H, s), 6.62 (2H, m),6.74 (1H, d).

DESCRIPTION 1212-{[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-[(methyloxy)methyl]phenol.(D121)

A mixture of 2-amino-4-[(methyloxy)methyl]phenol (D120) (37.5 mg, 0.245mmol),1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone(D73, 60 mg, 0.223 mmol), Polymer supported cyanoborohydride (185 mg,0.445 mmol) and acetic acid (0.064 mL, 1.114 mmol) in THF (3 mL) washeated to 100° C. for 40 mins (2×20 mins) in a microwave reactor. Themixture was diluted with EtOAc (5 mL) washed with dilute aq potassiumbicarbonate, water and brine, dried (MgSO₄) and concentrated to drynessin vacuo. The reside was purified by silica gel chromatography elutingwith DCM to 20% of 1:10 2M NH₃ in MeOH/DCM to yield the title compoundas a thick pale yellow oil. 58 mg, 57.6%

¹H NMR δ (CDCl₃): 1.35-1.61 (8H, m), 1.66-1.71 (2H, m), 1.86-1.91 (2H,m), 2.23-2.40 (2H, m), 2.89-2.98 (2H, m), 3.21 (1H, m), 3.37 (3H, s),3.43 (3H, s), 3.49 (3H, s), 3.53-3.66 (5H, m), 4.34 (2H, s), 6.55 (1H,br s), 6.67 (1H, br s).

LC/MS 407 (MH+), 405(M−H).

DESCRIPTION 1224-[(Methyloxy)methyl]-2-nitrophenyltrifluoromethanesulfonate. (D122)

A stirred mixture of 4-[(methyloxy)methyl]-2-nitrophenol D119 (1.15 g,6.28 mmol) and pyridine (0.762 mL, 9.42 mmol) in DCM (50 mL) under argonwas cooled to 0° C. and trifluoromethanesulfonic anhydride (1.167 mL,6.91 mmol) was added dropwise over 5 mins. The mixture was stirred at 0°C. for 10 mins and then at room temp for 1 hr before cooling back to 0°C. whereupon it was treated with 1N HCl (15 mL). the mixture was allowedto warm to rt, the organic phase separated washed with further 1N HCland brine, dried over MgSO₄, and then concentrated to dryness undervacuum to afford the title compound as a pale brown oil 1.95 g, 99%.

¹H NMR δ (CDCl₃): 3.47 (3H, s), 4.55 (2H, s), 7.42 (1H, d, J=8.4 Hz),7.68 (1H, d, J=8.4 Hz), 8.14 (1H, d).

DESCRIPTION 123 bis(1,1-Dimethylethyl){4-[(methyloxy)methyl]-2-nitrophenyl}propanedioate. (D123)

A stirred solution of bis(1,1-dimethylethyl) propanedioate (1.672 g,7.73 mmol) in anhydrous DMF (25 mL) under argon was cooled to 0° C. andtreated, portionwise with sodium hydride (0.297 g, 7.42 mmol) which wasadded over 10 mins. The resultant mixture was stirred at 0° C. for 15mins and then allowed to warm to rt. After 1 hr the mixture was cooledback to 0° C. and treated with a solution of4-[(methyloxy)methyl]-2-nitrophenyl trifluoromethanesulfonate D122 (1.95g, 6.19 mmol) in DMF (5 mL) which was added slowly over 10 mins. Afterthe addition was complete the cooling bath was removed and the mixtureallowed to warm to rt. After 1 hr TLC indicated little or no reaction.The mixture was then warmed to 70° C. for 16 hr, then cooled to roomtemp and the solvent was removed under vacuum. The dark brown oilyreside was dissolved in EtOAc (100 mL) and washed thoroughly with water(6×50 mL) and brine (50 mL), dried (MgSO₄) and concentrated to drynessunder vacuum. The residue was subjected to silica gel chromatographyeluting with 0-5% MeOH in DCM to give the title compound as a yellow oil(1.32 g, 55.9%).

¹H NMR δ (CDCl₃, 400 MHz): 1.45-1.51 (18H, m), 3.42 (3H, s), 4.52 (2H,s), 5.09 (1H, s), 7.51 (1H, d), 7.59 (1H, m), 8.01 (1H, d).

DESCRIPTION 124 bis(1,1-Dimethylethyl){2-amino-4-[(methyloxy)methyl]phenyl}propanedioate. (D124)

A mixture of bis(1,1-dimethylethyl){4-[(methyloxy)methyl]-2-nitrophenyl}propanedioate (D123) (1.30 g, 3.41mmol) and palladium on carbon (0.181 g, 0.170 mmol) in ethanol (30 mL)was stirred under hydrogen at atmospheric pressure for 16 hr. Thecatalyst was removed by filtration through celite and the filtrateconcentrated to dryness under vacuum to afford the crude title compoundas a thick yellow oil 1.15 g, 96%.

¹H NMR δ (CDCl₃, 400 MHz): 1.42-1.51 (18H, m), 3.37 (3H, s), 4.12 (2H,br s), 4.35 (2H, s), 4.46 (1H, s), 6.71 (2H, m), 7.13 (1H, d).

DESCRIPTION 125 4-Hydroxy-3-nitrobenzamide. (D125)

A mixture of methyl 4-hydroxy-3-nitrobenzoate (1.00 g, 5.07 mmol) andconcentrated aq ammonia (10.0 mL, 162 mmol) was heated to 100° C. for 90mins (3×30 mins) in a microwave reactor. The mixture was poured intowater (70 mL), acidified with 6N HCl and extracted with EtOAc (4×25 mL).The combined extracts were dried (MgSO₄) and concentrated in vacuo. Theresidue was triturated with DCM (20 mL) filtered and washed with DCMbefore drying under vacuum to afford the crude title compound as ayellow solid 0.49 g, 53.0%

¹H NMR δ (DMSO-d₆, 400 MHz): 7.15 (1H, d), 7.36 (1H, s), 8.00-8.05 (2H,m), 8.42 (1H, s), 11.75 (1H, br s)

DESCRIPTION 126 3-Amino-4-hydroxybenzamide. (D126)

A mixture of 4-hydroxy-3-nitrobenzamide D125 (0.49 g, 2.69 mmol),cyclohexene (1.105 g, 13.45 mmol) and 10% palladium on carbon (0.143 g,0.135 mmol) in ethanol (20 mL) was heated to reflux under argon for 3hr. The cooled mixture was filtered through celite and the filtrateconcentrated to dryness in vacuo to afford a yellow/brown solid. Theproduct was purified by silica gel chromatography eluting with 0-15% 2Mammonia in MeOH/DCM. The title compound was isolated as a pale brownpowder, 0.26 g, 57.2%.

¹H NMR δ (d⁶DMSO, 400 MHz): 4.36 (2H, br s), 6.63 (1H, d), 6.89 (1H, s),6.96 (1H, m), 7.13 (1H, d), 7.53 (1H, s), 9.50 (1H, br s)

DESCRIPTION 1273-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-hydroxybenzamide.(D127)

A mixture of 3-amino-4-hydroxybenzamide (D126) (47.7 mg, 0.313 mmol),1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinone (75 mg, 0.313mmol), polymer supported cyanoborohydride (260 mg, 0.627 mmol) andacetic acid (0.090 mL, 1.567 mmol) in THF (3 mL) was heated to 100° C.for 40 mins (2×20 mins) in a microwave reactor. The mixture was dilutedwith EtOAc (5 mL) washed with dilute aq potassium bicarbonate, water andbrine, dried (MgSO₄) and concentrated to dryness in vacuo. The residewas purified by silica gel chromatography eluting with DCM to 20% 3:102M NH₃ in MeOH/DCM. The title compound was isolated as a colourlesssolid, 51 mg, 41.2%.

¹H NMR δ (CD₃OD): 1.18 (3H, t), 1.23-1.58 (7H, m), 1.73 (2H, m), 1.95(2H, m), 2.10 (2H, d), 2.44 (2H, t), 3.12 (2H, d), 3.29-3.41 (7H, m),3.47-3.52 (2H, m), 6.68 (1H, d J=8.4 Hz), 7.11 (1H, d J=8.4 Hz), 7.16(1H, d), [OH not visible].

LC/MS 376 (MH⁺), 374(M−H).

DESCRIPTION 1284-Hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzamide.(D128)

A mixture of 3-amino-4-hydroxybenzamide (D126) (33.9 mg, 0.223mmol),1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone(60 mg, 0.223 mmol), polymer supported cyanoborohydride (185 mg, 0.445mmol) and acetic acid (0.064 mL, 1.114 mmol) in THF (3 mL) was heated to100° C. for 40 mins (2×20 mins) in a microwave reactor. The mixture wasfiltered, diluted with EtOAc (5 mL) washed with dilute aq potassiumbicarbonate, water and brine, dried (MgSO₄) and concentrated to drynessin vacuo. The residue was purified by silica gel chromatography elutingwith 0-10% 2M NH₃ in MeOH/DCM. The title compound was isolated as acolourless solid 29 mg, 28.9%.

¹H NMR δ (CDCl₃): 1.49-1.70 (10H, m), 1.85-1.91 (4H, m), 2.23-2.32 (4H,m) 3.14 (2H, m), 3.40-3.54 (5H, m), 3.56 (4H, dd), 4.10 (1H, m), 4.47(2H, s), 7.04 (1H, d), 7.15 (2H, m).

LC/MS 406 (MH+), 404(M−H).

DESCRIPTION 129 4-(2-Methyl-1,3-dioxolan-2-yl)-2-nitrophenol. (D129)

A stirred mixture of 1-(4-hydroxy-3-nitrophenyl)ethanone (3.00 g, 16.56mmol), ethylene glycol (1.385 mL, 24.84 mmol) and p-toluenesulfonic acidmonohydrate (0.158 g, 0.828 mmol) in toluene (60 mL) was heated toreflux for 18 hr in a 250 mL round bottom flask fitted with a Dean-Starkapparatus. The mixture was cooled and diluted with EtOAc (80 mL) andthen washed with water (3×30 mL) and brine (20 mL), dried (Na₂SO₄) andconcentrated to dryness in vacuo to afford a thick brown oily residue.This was purified by silica gel chromatography eluting with 5-50% Et₂Oin isohexane. The title product was isolated as a yellow oil (2.41 g,64.6%).

¹H NMR δ (CDCl₃, 400 MHz): 1.64 (3H, s), 3.83 (4H, q), 4.06 (4H, q),7.14 (1H, d), 7.69 (1H, d), 8.23 (1H, d), 10.57 (1H, s).

DESCRIPTION 130 2-Amino-4-(2-methyl-1,3-dioxolan-2-yl)phenol. (D130)

A stirred mixture of 4-(2-methyl-1,3-dioxolan-2-yl)-2-nitrophenol D129(2.40 g, 10.66 mmol), cyclohexene (4.38 g, 53.3 mmol) and 10% palladiumon carbon (0.227 g, 0.213 mmol) in ethanol (75 mL) was heated to refluxfor 6 hr under argon. The mixture was cooled to rt and the catalyst wasremoved by filtration through celite. The filtrate was concentrated todryness in vacuo and the reside dissolved in 10% MeOH in DCM (20 mL) andpassed through a SCX-2 cartridge (25 g) which was then eluted withfurther 10% MeOH in DCM to wash through any unreacted starting materialand then with 2M ammonia in MeOH. The basic eluate was concentratedunder vacuum to give the title compound as a yellow-brown solid (1.58 g,76%).

¹H NMR δ (DMSO-d_(s), 400 MHz) 2.44 (3H, s), 3.44 (4H, s) (note: partlyobscured by water signal), 3.74 (2H, br s), 6.69 (1H, d), 7.53 (1H, s),7.12 (1H, d), 7.21 (1H, s), 9.30 (1H, br s)

DESCRIPTION 1311-(4-Hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}-cyclohexyl)-4-piperidinyl]amino}phenyl)ethanone.(D131)

A mixture of 2-amino-4-(2-methyl-1,3-dioxolan-2-yl)phenol D130 (43.5 mg,0.223 mmol),1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone(D73, 60 mg, 0.223 mmol), polymer supported cyanoborohydride (185 mg,0.445 mmol) and acetic acid (0.019 mL, 0.334 mmol) in THF (3 mL) washeated in a microwave reactor to 100° C. for 60 mins (3×20 mins). Thecooled mixture was diluted with EtOAc (5 mL) and washed with dilute aqpotassium carbonate and brine, dried (MgSO₄), then concentrated todryness in vacuo. The residue was subjected to chromatography on silicagel eluting with DCM to DCM/MeOH/NH₄OH (90/9/1). The crude title productwas isolated as a sticky brown gum (32 mg, 32.0%), the product was takenforward to the next step in the synthesis without further purification.

LC/MS 405 (MH)⁺, 403(M−H)⁺.

DESCRIPTION 132 1-(3-Amino-4-hydroxyphenyl)ethanone O-methyloxime.(D132)

A mixture of O-methylhydroxylamine hydrochloride (535 mg, 6.40 mmol),2-amino-4-(2-methyl-1,3-dioxolan-2-yl)phenol D130 (250 mg, 1.28 mmol)and potassium carbonate (442 mg, 3.20 mmol) in ethanol (10 mL) washeated to reflux for 2 hr. The mixture was cooled to rt and concentratedto dryness under vacuum and the residue partitioned between DCM andwater. The organic phase was separated washed with brine, dried (MgSO₄)and concentrated to dryness in vacuo. The residue was purified usingsilica gel chromatography eluting with 0 to 10% MeOH in DCM. The titleproduct was isolated as a pale brown solid, 224 mg, 97%.

¹H NMR δ (CDCl₃, 400 MHz): 2.03 (3H, s), 3.84 (3H, s), 4.61 (2H, br s),6.62 (1H, d), 6.69 (1H, d), 6.89 (1H, d), 9.33 (1H, br s).

DESCRIPTION 1331-(4-Hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}phenyl)ethanoneO-methyloxime. (D133)

A mixture of 1-(3-amino-4-hydroxyphenyl)ethanone O-methyloxime (D132)(33 mg, 0.183 mmol),1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone(D73, 49.3 mg, 0.183 mmol), polymer supported cyanoborohydride (152 mg,0.366 mmol) and acetic acid (0.052 mL, 0.916 mmol) in dichloromethane(DCM) (3 mL) was heated to 100° C. for 30 mins in a microwave reactor.The mixture was washed with dilute aq potassium carbonate dried (MgSO₄)and concentrated to dryness under vacuum. The residue was purified bysilica gel chromatography eluting with DCM/MeOH/NH₄OH (90:9:1). Thetitle product was isolated as a v pale yellow gum, 40 mg, 50.4%.

LC/MS 434 (MH)⁺, 432(M−H)⁺.

DESCRIPTION 134 2-Bromo-4-cyanophenylacetic acid. (D134)

A solution of 4-cyanophenylacetic acid (1.6 g, 9.93 mmol) in 50% aqueoussulfuric acid (10 mL) was treated with N-bromosuccinimide (1.8 g, 10.11mmol). The mixture was stirred in the dark for 18 h then diluted withwater and extracted with diethyl ether to give2-bromo-4-cyanophenylacetic acid (2.1 g, 7.00 mmol, 70.5% yield) as awhite solid containing about 25% of starting material.

[M—CO₂H]⁻ 194 and 196

DESCRIPTION 135 N-Boc4-{[(2-Bromo-4-cyanophenyl)acetyl]amino}piperidine. (D135)

A mixture of 3-bromo-4-cyanophenylacetic acid (D134, 2.1 g, 7.00 mmol),1-Boc 4-aminopiperidine (1.5 g, 7.49 mmol), EDC hydrochloride (1.5 g,7.82 mmol), diisopropylethylamine (3.0 mL, 17.22 mmol), and DMF (25 mL)was stirred for 2 h at room temperature then diluted with ethyl acetateand washed with aqueous citric acid, aqueous sodium bicarbonate, water,and brine. Crystallisation from diethyl ether gave N-Boc4-{[(2-bromo-4-cyanophenyl)acetyl]amino}piperidine (1.5 g, 2.84 mmol,40.6% yield) as a white solid containing about 20% of N-Boc4-{[(4-cyanophenyl)acetyl]amino}piperidine.

M−H⁻ 420 and 422

DESCRIPTION 136 N-Boc4-(6-Cyano-2-oxo-2,3-dihydro-1H-indol-1-yl)-piperidine. (D136)

A solution of N-Boc 4-{[(2-bromo-4-cyanophenyl)acetyl]amino}piperidine(D135, 100 mg, 0.189 mmol) in anhydrous degassed tert-butanol (2 mL) wastreated with X-PHOS (10 mg, 0.021 mmol), potassium carbonate (70 mg,0.506 mmol), palladium (II) acetate (2 mg, 8.91 μmol), and phenylboronicacid (2 mg, 0.016 mmol), then heated at 85° C. for 1 h then cooled andevaporated. Chromatography on silica (20 g), eluting with 10-50% ethylacetate—isohexane, gaveN-Boc-4-(6-cyano-2-oxo-2,3-dihydro-1H-indol-1-yl)-piperidine (40 mg,0.117 mmol, 61.8% yield) as a colourless oil.

[M−H]⁻ 340.

DESCRIPTION 137 4-(6-Cyano-2-oxo-2,3-dihydro-1H-indol-1-yl)-piperidinehydrochloride. (D137)

A solution of N-Boc4-(6-cyano-2-oxo-2,3-dihydro-1H-indol-1-yl)-piperidine (D136, 400 mg,1.172 mmol) in dichloromethane (5 mL) was treated with 4M HCl in dioxane(5 mL, 20.00 mmol). After 4 h at room temperature, evaporation andcrystallisation from diethyl ether gave white crystals of4-(6-cyano-2-oxo-2,3-dihydro-1H-indol-1-yl)-piperidine hydrochloride(270 mg, 0.972 mmol, 83% yield).

MH⁺ 242

DESCRIPTION 138 5-Fluoro-3-(4-piperidinyl)-1,3-benzoxazol-2(3H)-onehydrochloride. (D138)

The title compound can be prepared using a similar methodology to thatdescribed for the 6-chloro analogue (E82 in WO9528397).

DESCRIPTION 139 (4-Methyl-2-nitrophenyl)methanol. (D139)

To a stirred solution of 4-methyl-2-nitrobenzoic acid (5 g, 27.6 mmol)in tetrahydrofuran (THF) (27 mL) was added borane tetrahydrofurancomplex (35.9 mL, 35.9 mmol) and the mixture stirred at reflux for 3hours. After cooling, the reaction mixture was extracted with water andDCM. The combined organic layers were dried over MgSO₄ and thenevaporated to dryness to give the alcohol (D139) as a pale yellow solid(4.52 g, 98%) which was used without further purification.

¹H-NMR (CDCl₃) δ: 2.45 (s, 3H), 4.89-4.91 (d, 2H), 7.44-7.48 (dd, 1H),7.55-7.59 (d, 1H), 7.90-7.91 (s, 1H).

LC/MS Retention time=2.67 min. (100%) (no ionisation)

DESCRIPTION 140 4-Methyl-2-nitrobenzaldehyde. (D140)

(4-Methyl-2-nitrophenyl)methanol D139 (1.028 g, 6.15 mmol), pyridiniumdichromate (3.47 g, 9.22 mmol)+molecular sieves (7 g, 6.15 mmol) in drydichloromethane (DCM) (14 mL) was stirred under argon at R.T. overnight.The reaction mixture was filtered by silica/kieselguhr (1:1) andextracted with water and DCM. Organic layers were combined andevaporated to give a pale yellow solid which was used without furtherpurification (0.665 g, 65.5%).

¹H-NMR (CDCl₃): δ2.54 (s, 3H), 7.57-7.6 (m, 1H), 7.86-7.9 (m, 2H), 10.49(s, 1H).

LC/MS Retention time=3.01 min. (100%) (no ionisation)

DESCRIPTION 141 Ethyl (2E)-3-(4-methyl-2-nitrophenyl)-2-propenoate.(D141)

To sodium hydride (1.593 g, 39.8 mmol) was added THF (39 mL) dropwiseand the reaction mixture cooled to −10° C. Triethyl phosphonoacetate(7.90 mL, 39.8 mmol) was added dropwise to give a colourless solution,maintaining the temperature at −10° C. The reaction mixture was allowedto warm to R.T. and the reaction mixture stirred for 30 mins. A solutionof 4-methyl-2-nitrobenzaldehyde D140 (2.192 g, 13.27 mmol) in THF (39mL) was added to give a dark yellow solution and the reaction mixturewas heated at reflux for 90 mins. The solution turned a dark red/brown.After this time, the reaction mixture was allowed to cool to R.T. TLCshowed all s.m. disappeared, product and a baseline impurity (DCM). Thereaction mixture was diluted with water (32 mL) and extracted intodiethyl ether (3×30 mL) and the organic layer dried over MgSO₄. Thereaction mixture was filtered and evaporated to dryness. The crudeproduct was purified by flash chromatography and was eluted with DCM togive the title compound as a yellow oil. Oil was triturated withiso-hexane to give a pale yellow solid (1.18 g, 37.8%).

¹H-NMR (CDCl₃) δ: 1.31-1.39 (t, 3H), 2.47 (s, 3H), 4.26 (q, 2H),6.32-6.36 (d, 1H), 7.25-7.26 (d, 1H), 7.43-7.45 (d, 1H), 7.83-7.84 (d,1H), 8.04-8.09 (d, 1H).

DESCRIPTION 142 Ethyl (2E)-3-(2-amino-4-methylphenyl)-2-propenoate.(D142)

Ethyl (2E)-3-(4-methyl-2-nitrophenyl)-2-propenoate D141 (0.500 g, 2.126mmol), iron (0.593 g, 10.63 mmol) and ammonium chloride (0.057 g, 1.063mmol) in ethanol (11 mL) and water (2 mL) was heated at reflux for 2hours. The mixture was cooled and filtered through a pad of kieselguhr.The filtrate was concentrated and the residue diluted with ethylacetate, washed with water and dried (MgSO₄). Filtration and evaporationof solvent afforded a bright yellow solid (0.417 g, 96%).

¹H-NMR (CDCl₃) δ: 1.31-1.34 (t, 3H), 2.27 (s, 3H), 3.92 (s, br, 2H),4.19-4.31 (q, 2H), 6.29-6.36 (d, 1H), 6.58 (s, 1H), 6.58-6.6 (dd, 1H),7.28-7.32 (dd, 1H), 7.77-7.83 (d, 1H).

LC/MS Retention time=3.32 min. (92%) (no ionisation).

DESCRIPTION 143 Ethyl(2E)-3-[2-({1-[4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-amino)-4-methylphenyl]-2-propenoate.(D143)

1-[4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8) (0.350 g, 1.462mmol)+ethyl (2E)-3-(2-amino-4-methylphenyl)-2-propenoate (D142) (0.1 g,0.487 mmol) were placed in a microwave vial with 1,2-dichloroethane(DCE) (0.974 mL) and stirred for 10 mins. Sodium triacetoxyborohydride(0.387 g, 1.827 mmol) was added and the mixture heated at 140° C. for 10mins. LCMS of the crude reaction mixture showed product (67% by u.v.).The reaction was quenched with NaHCO₃ (10 mL, sat. aq) and thenextracted with DCM (3×20 mL). The organic phases were combined, dried(phase sep. cartridge) and passed through a SCX-3 cartridge, elutingwith DCM/MeOH to remove any neutral/acidic by-products. The product waseluted from the cartridge with 0.5 M NH₃/MeOH to give a dark yellow oil.The crude product was purified by column chromatography using a 5 gcartridge and eluting with DCM-8% NH₃/MeOH/DCM to give the product as abright yellow/green oil (0.117 g, 56%).

LC/MS 429 (MH⁺), retention time=2.69 mins.

DESCRIPTION 144 Ethyl342-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-methylphenyl]propanoate.(D144)

Ethyl(2E)-3-[2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-methyl-phenyl]-2-propenoateD143 (0.117 g, 0.273 mmol) was dissolved in ethanol (16 mL) and passedover a Pd/C cartridge on the H-cube, temp. 45° C., pressure 50 psi. witha flow rate of 0.5 mL/min. LCMS showed double bond reduced and some s.m.remaining. The solution was passed through the H-cube again, same temp.and pressure as before. LCMS showed reaction had gone to completion. Thesolvent was removed in vacuo to give a pale brown oil.

LC/MS 431 (MH+), retention time=2.64 min.

DESCRIPTION 145 2-Amino-6-methyl-3-pyridinol. (D145)

A mixture of 3-hydroxy-6-methyl-2-nitropyridine (4.2 g, 27 mmol) and 10%palladium on carbon (0.25 g, 0.24 mmol) in ethanol (75 mL) was stirredat rt under an atmosphere of hydrogen for 24 hr. The catalyst wasremoved by filtration through celite and the filtrate concentrated todryness under vacuum. The residue was subjected to chromatography onsilica gel using Biotage SP1 employing a 40+M cartridge and eluting withMeOH/DCM 10% 2 CV, 10-35% in 10 CV, 35% 2 CV. The purified product2-amino-6-methyl-3-pyridinol (D145, 2.72 g, 80%) was isolated as palebrown solid.

[M+H]⁺125

DESCRIPTION 1462-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-6-methyl-3-pyridinol.(D146)

Polymer supported sodium cyanoborohydride (99 mg, 0.43 mmol) was addedto a solution of1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinone (D8, 51 mg,0.21 mmol), 2-amino-6-methyl-3-pyridinol (D145, 26 mg, 0.21 mmol) andacetic acid (0.061 mL, 1.07 mmol) in THF (2.5 mL). The mixture washeated by microwave at 100° C. for 30 min and then for a further 30 minbefore being filtered and concentrated by rotary evaporation to give2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-6-methyl-3-pyridinol(D146, 82 mg, 100%) as a yellow oil, which was used without furtherpurification.

¹H NMR (CDCl₃) δ: 1.16-1.24 (4H, m), 1.45-1.74 (6H, m), 1.82-1.96 (3H,m), 2.32 (3H, s), 2.43 (3H, m), 2.85 (3H, m), 3.41 (1H, m), 3.45-3.52(3H, m), 6.24 (1H, d, J 8.1), 6.99 (1H, d, J 8.1).

DESCRIPTION 147 2-Fluoro-4-hydroxy-5-nitrobenzonitrile. (D147)

Nitric acid (0.326 mL, 7.29 mmol) 70% was added dropwise to a stirredsolution of 2-fluoro-4-hydroxybenzonitrile (1 g, 7.29 mmol) in aceticacid (20 mL). The resulting solution was warmed to 40° C. for 24 hr.Solvent removed under reduced pressure to afford a yellow solid.Recrystallisation from EtOH (˜15 mL) afforded2-fluoro-4-hydroxy-5-nitrobenzonitrile (401 mg, 2.202 mmol, 30.2% yield)as a yellow solid.

¹H NMR δ (CDCl₃): 7.04 (1H, d, J=9.6 Hz), 8.52 (1H, d, J=6.4 Hz), 11.10(1H, s).

DESCRIPTION 148 5-Amino-2-fluoro-4-hydroxybenzonitrile. (D148)

A solution of 2-fluoro-4-hydroxy-5-nitrobenzonitrile (D147; 270 mg,1.483 mmol) in ethanol (35 mL) was passed through an H-Cube flowhydrogenator at room temperature and atmospheric pressure on full H₂mode, with a flow rate of 1 mL min⁻¹ and using a CatCart30 (approx. 140mg catalyst). The residual solution was diluted with further ethanol (8mL) to ensure maximum recovery of material. The collected productsolution was evaporated to dryness to give the desired product as a tansolid (215 mg).

¹H NMR δ (CD₃OD): 6.58 (1H, dd, J=7.6, 3 Hz), 6.85 (1H, d, J=6.8 Hz).

EXAMPLE 13-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one hydrochloride. (E1)

Hünig's base (DIPEA) (100 μl, 0.573 mmol) was added to a solution of2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)phenol(D10, 82.6 mg, 0.248 mmol) in dichloromethane (4 mL) at rt under argon.The reaction was cooled to 0° C. and the triphosgene (35.6 mg, 0.120mmol) was added. The mixture was stirred for 1 h at 0° C. and then thereaction was quenched with saturated aqueous NaHCO₃ (10 mL) andpartitioned between dichloromethane and water. The aqueous layer wasextracted with dichloromethane (2×) and the combined organics were dried(Na₂SO₄) and concentrated by rotary evaporation to give a pale yellowoil. The residue was purified via chromatography (silica,dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) togive the free base of the title compound as a pale yellow solid. HCl(500 μl, 0.500 mmol, 1 M in diethyl ether) was added to a solution ofthe free base in dichloromethane (2 mL) at rt. The reaction was stirredfor 30 min before the solvent was removed by rotary evaporation to give3-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-onehydrochloride (E1, 82.4 mg, 80% yield) as a cream solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.10 (3H, t, J 6.8), 1.28-1.40 (5H, m), 1.78(2H, m), 1.95-2.11 (6H, m), 2.64-2.78 (2H, m), 3.16-3.28 (3H, m), 3.48(2H, q, J 6.8), 3.67 (2H, m), 4.56 (1H, m), 7.16 (1H, t, J 7.8), 7.26(1H, t, J 7.8), 7.37 (1H, d, J 8), 7.63 (1H, m), 9.54 (1H, m).

M+H⁺ 359

EXAMPLE 23-{1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-onehydrochloride. (E2)

Diisopropylethylamine (57.3 μl, 0.328 mmol) was added to a solution of2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)phenol(D18, 53.8 mg, 0.155 mmol) in dichloromethane (2.28 mL) at rt underargon. The reaction was cooled to 0° C. and the triphosgene (20.0 mg,0.067 mmol) was added. The mixture was stirred for 30 min at 0° C.,followed by a further 15 min at rt. The reaction was quenched withsaturated aqueous NaHCO₃ (10 mL) and partitioned between dichloromethaneand water. The aqueous layer was extracted with dichloromethane (2×) andthe combined organics were dried (Na₂SO₄) and concentrated by rotaryevaporation to give a pale yellow oil. The residue was purified viachromatography (silica, dichloromethane to 0.5% ammonia/9.5%methanol/90% dichloromethane) to give the free base of the titlecompound as a white solid. The free base was dissolved indichloromethane (1.45 mL) and methanol (724 μl) at 25° C. HCl (252 μl,0.252 mmol, 1 M in diethyl ether) was then added and the reaction wasstirred for 15 min. The solvent was removed by rotary evaporation togive3-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-onehydrochloride (E2, 49.5 mg, 70% yield) as a white solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 0.868 (3H, t, J 7.2), 1.28-1.40 (5H, m),1.44-1.55 (2H, m), 1.79 (2H, m), 1.97-2.11 (6H, m), 2.65-2.79 (2H, m),3.14-3.27 (3H, m), 3.83 (2H, q, J 7.2), 3.67 (2H, m), 4.57 (1H, m), 7.16(1H, m), 7.26 (1H, m), 7.37 (1H, d, J 8), 7.65 (1 H, d, J 7.6), 9.57(1H, m).

M+H⁺ 373

EXAMPLE 33-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilehydrochloride. (E3)

Diisopropylethylamine (0.1 mL, 0.573 mmol) was added to a solution of3-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-hydroxybenzonitrile(D20, 96.9 mg, 0.271 mmol) in dichloromethane (4 mL) at rt under argon.The reaction was cooled to 0° C. and the triphosgene (34.8 mg, 0.117mmol) was added. The mixture was stirred for 30 min at 0° C., followedby a further 15 min at rt. The reaction was quenched with saturatedaqueous NaHCO₃ (10 mL) and partitioned between dichloromethane andwater. The aqueous layer was extracted with dichloromethane (2×) and thecombined organics were dried (Na₂SO₄) and concentrated by rotaryevaporation to give a pale yellow oil. The residue was purified viachromatography (silica, dichloromethane to 0.5% ammonia/9.5%methanol/90% dichloromethane) to give the free base of the titlecompound as a white solid. The free base was dissolved indichloromethane (2.0 mL) and methanol (1 mL) at rt. HCl (0.35 mL, 0.350mmol, 1 M in diethyl ether) was added and the reaction stirred for 30min. The solvent was removed by rotary evaporation to give3-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilehydrochloride (E3, 72.3 mg, 61% yield) as a white solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.10 (3H, t, J 6.8), 1.22-1.40 (5H, m),1.89-2.11 (8H, m), 2.87 (2H, m), 3.13-3.29 (3H, m), 3.47 (2H, q, J 6.8),3.68 (2H, m), 4.61 (1H, m), 7.58 (1H, d, J 8.4), 7.69 (1H, dd, J 8.4 and1.2), 8.43 (1H, d, J1.2), 10.62 (1H, m).

M+H⁺ 384

EXAMPLE 43-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-fluoro-5-methyl-1,3-benzoxazol-2(3H)-onehydrochloride. (E4)

Hünig's base (0.12 mL, 0.687 mmol) was added to a solution of2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-5-fluoro-4-methylphenol(D23, 120 mg, 0.328 mmol) in dichloromethane (5 mL) at rt under argon.The reaction was cooled to 0° C. and the triphosgene (39.2 mg, 0.132mmol) was added. The mixture was stirred for 40 min at 0° C. and thenthe reaction was quenched with saturated aqueous NaHCO₃ (10 mL) andpartitioned between dichloromethane and water. The aqueous layer wasextracted with dichloromethane (2×) and the combined organics were dried(Na₂SO₄) and concentrated by rotary evaporation to give a yellow oil.The residue was purified via chromatography (silica, dichloromethane to0.5% ammonia/9.5% methanol/90% dichloromethane) to give the free base ofthe title compound as a colourless oil. HCl (0.53 mL, 0.53 mmol, 1 M indiethyl ether) was added to a solution of the free base in diethyl ether(5 mL) at rt. The reaction was stirred for 5 min before the solvent wasremoved by rotary evaporation to give3-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-fluoro-5-methyl-1,3-benzoxazol-2(3H)-onehydrochloride (E4, 108 mg, 73% yield) as a cream solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.10 (3H, t, J 6.8), 1.23-1.14 (5H, m),1.89-2.08 (8H, m), 2.27 (3H, s), 2.85 (2H, m), 3.13-3.27 (3H, m), 3.47(2H, q, J 6.8), 3.66 (2H, m), 4.55 (1H, m), 7.36 (1H, d, J 9.2), 7.95(1H, d, J 6.4), 10.42 (1H, m).

M+H⁺ 391

EXAMPLE 53-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-onehydrochloride. (E5)

Diisopropylethylamine (0.079 mL, 0.454 mmol) was added to a solution of2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-(methylsulfonyl)phenol(D24, 93.3 mg, 0.227 mmol) in dichloromethane (2.5 mL) at rt underargon. The reaction was cooled to 0° C. and the triphosgene (26.8 mg,0.09 mmol) was added. The mixture was stirred for 30 min at 0° C. Thereaction was quenched with saturated aqueous NaHCO₃ (5 mL) andpartitioned between dichloromethane and water. The aqueous layer wasextracted with dichloromethane (2×) and the combined organics were dried(Na₂SO₄) and concentrated by rotary evaporation to give a yellow oil.The residue was purified via chromatography (silica, dichloromethane to0.5% ammonia/9.5% methanol/90% dichloromethane) to give the free base ofthe title compound as a pale yellow solid. HCl (0.32 mL, 0.32 mmol, 1 Min diethyl ether) was added to a solution of the free base indichloromethane (2 mL) and the mixture stirred for 15 min. The solventwas removed by rotary evaporation and the residue triturated withdiethyl ether to give3-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-onehydrochloride (E5, 64 mg, 57% yield) as a white solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.10 (3H, t, J 6.8), 1.27-1.41 (5H, m), 1.83(2H, m), 1.99 (4H, m), 2.11 (2H, m), 2.75 (2H, m), 3.14-3.28 (3H, m),3.35 (3H, s), 3.70 (2H, m), 4.65 (1H, m), 7.62 (1H, d, J 8.4), 7.75 (1H,dd, J 8.4 and 1.6), 8.18 (1H, s), 9.83 (1 H, m). Note: 2H not visible inNMR spectrum as obscured by solvent or water.

M+H⁺ 437.

EXAMPLE 63-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(ethylsulfonyl)-1,3-benzoxazol-2(3H)-onehydrochloride. (E6)

Diisopropylethylamine (0.184 mL, 1.05 mmol) was added to a solution of2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-(ethylsulfonyl)phenol(D25, 211 mg, 0.497 mmol) in dichloromethane (9 mL) at rt under argon.The reaction was cooled to 0° C. and the triphosgene (60.9 mg, 0.205mmol) was added. The mixture was stirred for 30 min at 0° C., followedby a further 15 min at rt. The reaction was quenched with saturatedaqueous NaHCO₃ (15 mL) and partitioned between dichloromethane andwater. The aqueous layer was extracted with dichloromethane (2×) and thecombined organics were dried (Na₂SO₄) and concentrated by rotaryevaporation to give a brown oil. The residue was purified viachromatography (silica, dichloromethane to 0.5% ammonia/9.5%methanol/90% dichloromethane followed by amino-doped silica,iso-hexane-ethyl acetate) to give the free base of the title compound asa white solid. HCl (0.1 mL, 0.100 mmol, 1 M in diethyl ether) was addedto a solution of the free base in dichloromethane (1 mL) at rt. Thesolvent was removed by rotary evaporation and the resulting solidtriturated with diethyl ether (2×) to give3-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(ethylsulfonyl)-1,3-benzoxazol-2(3H)-onehydrochloride (E6, 19.7 mg, 8% yield) as a white solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.08-1.17 (6H, m), 1.27-1.41 (5H, m), 1.80(2H, m), 1.99 (4H, m), 2.12 (2H, m), 2.69 (2H, m), 3.12-3.26 (3H, m),3.69 (2H, m), 4.64 (1H, m), 7.63 (1H, d, J 8), 7.71 (1H, dd, J 8 and1.6), 8.05 (1H, d, J 2), 9.62 (1H, m). Note: 4 H not visible in NMRspectrum as obscured by solvent or water.

M+H⁺ 451.

EXAMPLE 75-Fluoro-3-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-onehydrochloride. (E7)

Diisopropylethylamine (0.219 mL, 1.25 mmol) was added to a solution of4-fluoro-2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)phenol(D26, 216 mg, 0.591 mmol) in dichloromethane (9 mL) at rt under argon.The reaction was cooled to 0° C. and the triphosgene (75 mg, 0.254 mmol)was added. The mixture was stirred for 30 min at 0° C., followed by afurther 15 min at rt. The reaction was quenched with saturated aqueousNaHCO₃ (15 mL) and partitioned between dichloromethane and water. Theaqueous layer was extracted with dichloromethane (2×) and the combinedorganics were dried (Na₂SO₄) and concentrated by rotary evaporation togive a pale yellow oil. The residue was purified via chromatography(silica, dichloromethane to 0.5% ammonia/9.5% methanol/90%dichloromethane followed by amino-doped silica, iso-hexane to ethylacetate) to give the free base of the title compound as a white solid.The free base was dissolved in dichloromethane (702 μl) at 25° C. HCl(81 μl, 0.081 mmol, 1 M in diethyl ether) was then added and thereaction was stirred for 15 min. The solvent was removed by rotaryevaporation to give a white solid that was then triturated with diethylether to give5-fluoro-3-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-onehydrochloride (E7, 17.8 mg, 6% yield) as a white solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 0.87 (3H, t, J 7.2), 1.26-1.41 (5H, m), 1.49(2H, m), 1.80 (2H, m), 1.96-2.12 (4H, m), 2.69 (2H, m), 3.12-3.26 (3H,m), 3.38 (3H, d, J 6.6), 3.68 (2H, m), 4.57 (1H, m), 6.99 (1H, m), 7.40(1H, m), 7.68 (1H, dd, J 8.8 and 2.4), 9.68 (1H, m).

M+H⁺ 391.

EXAMPLE 83-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-fluoro-1,3-benzoxazol-2(3H)-onehydrochloride. (E8)

Diisopropylethylamine (0.316 mL, 1.81 mmol) was added to a solution of2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-fluorophenol(D27, 299 mg, 0.853 mmol) in dichloromethane (9 mL) at rt under argon.The reaction was cooled to 0° C. and the triphosgene (104 mg, 0.352mmol) was added. The mixture was stirred for 30 min at 0° C., followedby a further 15 min at room temperature. The reaction was quenched withsaturated aqueous NaHCO₃ (15 mL) and partitioned between dichloromethaneand water. The aqueous layer was extracted with dichloromethane (2×) andthe combined organics were dried (Na₂SO₄) and concentrated by rotaryevaporation to give a brown oil. The residue was purified viachromatography (silica, dichloromethane to 0.5% ammonia/9.5%methanol/90% dichloromethane followed by amino-doped silica, iso-hexaneto ethyl acetate) to give the free base of the title compound as a whitesolid. The free base was dissolved in diethyl ether (1.5 mL) at 25° C.HCl (0.154 mL, 0.154 mmol, 1 M in diethyl ether) was then added and thereaction was stirred for 15 min. The solvent was removed by rotaryevaporation to give3-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-fluoro-1,3-benzoxazol-2(3H)-onehydrochloride (E8, 33.4 mg, 9% yield) as a white solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.10 (3H, t, J 6.8), 1.25-1.42 (5H, m), 1.87(2H, m), 1.95-2.12 (6H, m), 2.77 (2H, m), 3.12-3.27 (3H, m), 3.47 (2H,q, J 6.8), 3.67 (2H, m), 4.57 (1H, m), 6.99 (1H, m), 7.39 (1H, m), 7.82(1H, dd, J 9.2 and 2.8), 10.12 (1H, m).

M+H⁺ 377.

EXAMPLE 93-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(methyloxy)-1,3-benzoxazol-2(3H)-onehydrochloride. (E9)

Diisopropylethylamine (81 μl, 0.466 mmol) was added to a solution of2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-(methyloxy)phenol(D28, 79.7 mg, 0.22 mmol) in dichloromethane (3.23 mL) at rt underargon. The reaction was cooled to 0° C. and the triphosgene (28.1 mg,0.095 mmol) was added. The mixture was stirred for 30 min at 0° C.,followed by a further 15 min at rt. The reaction was quenched withsaturated aqueous NaHCO₃ (10 mL) and partitioned between dichloromethaneand water. The aqueous layer was extracted with dichloromethane (2×) andthe combined organics were dried (Na₂SO₄) and concentrated by rotaryevaporation to give a pale yellow oil. The residue was purified viachromatography (silica, dichloromethane to 0.5% ammonia/9.5%methanol/90% dichloromethane) to give the free base of the titlecompound as an orange-yellow oil. The free base was dissolved in diethylether (2.34 mL) at 25° C. HCl (272 μl, 0.272 mmol, 1 M in diethyl ether)was then added and the reaction was stirred for 15 min. The solvent wasremoved by rotary evaporation to give a white solid that was thentriturated with diethyl ether to give3-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(methyloxy)-1,3-benzoxazol-2(3H)-onehydrochloride (E9, 46.9 mg, 45% yield) as a white solid.

¹H NMR δ (CDCl₃, 400 MHz) 1.2 (3H, m), 1.35-1.49 (5H, m), 1.98-2.11 (4H,m), 2.15 (2H, m), 2.43 (2H, m), 2.90 (2H, m), 3.38-3.59 (5H, m), 3.82(2H, m), 4.00 (3H, s), 4.57 (1H, m), 6.68 (1H, dd, J 8.8 and 2.4), 7.08(1H, d, J 8.8), 7.71 (1H, d, J 2.4).

M+H⁺ 389.

EXAMPLE 103-{1-[trans-4-(Ethyloxy)cyclohexyl]-4-piperidinyl}-5-methyl-1,3-benzoxazol-2(3H)-onehydrochloride. (E10)

Diisopropylethylamine (0.24 mL, 1.37 mmol) was added to a solution of2-({1-[trans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}amino)-4-methylphenol(D29, 215 mg, 0.648 mmol) in dichloromethane (8 mL) at rt under argon.The reaction was cooled to 0° C. and the triphosgene (79 mg, 0.267 mmol)was added. The mixture was stirred for 30 min at 0° C., followed by afurther 15 min at rt. The reaction was quenched with saturated aqueousNaHCO₃ (10 mL) and partitioned between dichloromethane and water. Theaqueous layer was extracted with dichloromethane (2×) and the combinedorganics were dried (Na₂SO₄) and concentrated by rotary evaporation togive a white solid. The residue was purified via chromatography (silica,dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) togive the free base of the title compound as a white solid. The free basewas dissolved in diethyl ether (1.5 mL) at 25° C. HCl (0.207 mL, 0.207mmol, 1 M in diethyl ether) was then added and the reaction was stirredfor 15 min. The solvent was removed by rotary evaporation to give3-{1-[trans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}-5-methyl-1,3-benzoxazol-2(3H)-onehydrochloride (E10, 39.3 mg, 14% yield) as a white solid.

¹H NMR δ (DMSO-d_(s), 400 MHz) 1.10 (3H, t, J 6.8), 1.24-1.40 (2H, m),1.54 (2H, m), 2.0-2.16 (6H, m), 2.66 (3H, s), 2.73 (2H, m), 3.15-3.30(4H, m), 3.42-3.58 (4H, m), 4.15 (1 H, m), 6.96 (1H, d, J 8), 7.23 (1H,d, J 8), 7.55 (1H, s), 10.22 (1H, m).

M+H⁺ 359.

EXAMPLE 114-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-2H-1,4-benzoxazin-3(4H)-onehydrochloride. (E11)

Sodium tert-butoxide (123 mg, 1.28 mmol) was added to a solution of2-chloro-N-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-N-(2-hydroxy-5-methylphenyl)acetamide(D31, 186 mg, 0.439 mmol) in tetrahydrofuran (5 mL) at rt under argon.The mixture was stirred overnight and then partitioned betweendichloromethane and saturated aqueous NaHCO₃. The aqueous layer wasextracted with dichloromethane (2×) and the combined organics were dried(Na₂SO₄) and concentrated by rotary evaporation to give a brown solid.The residue was purified via chromatography (silica, dichloromethane to0.5% ammonia/9.5% methanol/90% dichloromethane followed by amino-dopedsilica, iso-hexane to ethyl acetate) to give the free base of the titlecompound as a pale yellow solid. HCl (0.33 mL, 0.330 mmol, 1 M indiethyl ether) was added to a solution of the free base indichloromethane (2 mL) at rt. The solvent was removed by rotaryevaporation and the resulting solid triturated with diethyl ether togive4-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-2H-1,4-benzoxazin-3(4H)-onehydrochloride (E11, 60.7 mg, 31% yield) as a pale yellow solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.10 (3H, t, J 7.2), 1.24-1.39 (5H, m), 1.79(2H, m), 1.96 (6H, m), 2.33 (3H, s), 2.95 (2H, m), 3.11-3.22 (3H, m),3.47 (2H, q, J 7.2), 3.57-3.66 (2H, m), 4.42-4.54 (3H, m), 6.84 (1H, d,J 8), 6.92 (1H, d, J 8), 7.35 (1H, s), 9.38 (1H, m).

M+H⁺ 387.

EXAMPLE 12a3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilehydrochloride. (E12a)

Diisopropylethylamine (0.04 mL, 0.229 mmol) was added to a solution of4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile(D36, 37.5 mg, 0.097 mmol) in dichloromethane (2.5 mL) at rt underargon. The reaction was cooled to 0° C. and triphosgene (13.6 mg, 0.046mmol) was added. The mixture was stirred for 1 h at 0° C. The reactionwas quenched with saturated aqueous NaHCO₃ (5 mL) and partitionedbetween dichloromethane and water. The aqueous layer was extracted withdichloromethane (2×) and the combined organics were dried (Na₂SO₄) andconcentrated by rotary evaporation to give a pale yellow solid. Theresidue was purified via chromatography (silica, Biotage 12S column,dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) togive the free base of the title compound as a colourless oil. HCl (0.1mL, 0.1 mmol, 1 M in diethyl ether) was added to a solution of the freebase in dichloromethane (0.5 mL) and the solvent removed by rotaryevaporation. The resulting residue was triturated with diethyl ether(2×) to give3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilehydrochloride (E12a, 11.2 mg, 24% yield) as a cream solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.25-1.40 (5H, m), 1.84 (2H, m), 1.96-2.12(6H, m), 2.74 (2H, m), 3.13-3.29 (6H, m), 3.42 (2H, m), 3.55 (2H, m),3.69 (2H, m), 4.59 (1H, m), 7.59 (1H, d, J 8.4), 7.69 (1H, dd, J 8.4 and1.6), 8.22 (1H, d, J1.6), 9.95 (1H, m).

M+H⁺ 414.

EXAMPLE 12b3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilefree base. (E12b)

N.B. free base was also isolated en route to the HCl salt produced inE12a.

Hunig's Base (0.5 mL, 2.86 mmol) was added to a solution of4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile(D36-alternative procedure, 554 mg, 1.43 mmol) in DCM (10 mL) at rtunder Ar. The reaction was cooled to 0° C. and triphosgene (180 mg, 0.61mmol) was added. The mixture was stirred for 2 h at 0° C. The reactionwas quenched with sat. NaHCO₃ (10 mL) and partitioned between DCM andH₂O. The aqueous layer was extracted with DCM (2×) and the combinedorganics were dried (Na₂SO₄) and concentrated by rotary evaporation togive a yellow solid. The residues were purified via flash columnchromatography (silica, Biotage 40+S column, DCM to 0.5% NH₃/9.5%MeOH/90% DCM) to give 3-[1-(trans-1-methyl-4-{[2(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilefree base (E12b, 421 mg, 64%) as an off-white solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 0.87 (3H, s), 1.36-1.59 (6H, m), 1.73-1.86(4H, m), 2.12-2.24 (4H, m), 3.00-3.07 (2H, m), 3.26 (3H, s), 3.40-3.51(5H, m), 4.07 (1H, m), 7.54 (1H, d, J 8.3), 7.65 (1H, dd, J 8.3 and1.5), 7.97 (1H, d, J1.5).

LCMS: [M+H]⁺ 414.

EXAMPLE 12c3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilehydrochloride. (E12c)

HCl (1.3 mL, 1.3 mmol, 1 M in Et₂O) was added to a solution of3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilefree base (E12b, 270 mg, 0.65 mmol) in DCM (3 mL) at rt. The reactionwas stirred for 5 min, then the solvent was removed by rotaryevaporation and the residue triturated with Et₂O to give3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilehydrochloride (E12c, 265 mg, 81%) as an off-white solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.27-1.39 (5H, m), 1.78-1.89 (2H, m),1.95-2.12 (6H, m), 2.68-2.81 (2H, m), 3.12-3.28 (6H, m), 3.40-3.45 (2H,m), 3.53-3.58 (2H, m), 3.65-3.73 (2H, m), 4.60 (1H, m), 7.59 (1H, d, J8.4), 7.70 (1H, dd, J 8.4 and 1.4), 8.22 (1H, d, J 1.4), 9.95 (1H, m).

LCMS: [M+H]⁺ 414.

EXAMPLE 12d3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilefree base. (E12d)

To a solution of4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile(D80) (26.33 g, 67.9 mmol) in dry dichloromethane (DCM) (400 mL), DIPEA(23.73 mL, 136 mmol) was added at room temperature under argon. Thereaction was chilled at 0° C. and then triphosgene (8.67 g, 29.2 mmol)was added portionwise. Reaction mixture was allowed to stir at 0° C. for1 h then at room temperature for an additional hour. Reaction mixturewas quenched with saturated solution NaHCO₃ (200 mL), phases wereseparated and the aqueous one back extracted with DCM (2×300 mL).Combined organics were dried over Na₂SO₄ and evaporated to dryness togive crude material, 31 g, as pale yellow semisolid. Further 3.4 g ofcrude material were obtained in a similar way starting from 3.24 g of4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile.The two crude batches were combined and purified by SiO₂ FC eluting withDCM/MeOH/NH₄OH from 98/2/05 to 96/4/0.5 to 90/10/1. Evaporation ofvolatiles afforded title material (E12d, 27 g; 85%) as white crystallinesolid.

¹H NMR δ (CDCl₃, 400 MHz): 0.95 (3H, s), 1.58 (4H, m), 1.68 (2H, m),1.89 (4H, m), 2.23 (4H, m), 3.18 (2H, d), 3.41 (3H, s), 3.50 (1H, m),3.57 (2H, m), 3.62 (2H, m), 4.13 (1H, m), 7.29 (1H, d), 7.47 (1H, dd),7.47 (1H, s).

MH⁺=414.1.

EXAMPLE 12e3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilehydrochloride. (E12e)

To a solution of3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile(E12d) (10 g, 24.18 mmol) in dichloromethane (DCM) (100 mL), cooled at0° C. under an Argon atmosphere, HCl 1M in Et₂O (48.4 mL, 48.4 mmol) wasadded dropwise. The slurry was left stirring 30 min at 0° C. then 30min. at room temperature. White solid precipitation occurred. Slurry wasthen cautiously evaporated under reduced pressure with no bath heating.Obtained solid was triturated with Et₂O (100 mL) for 20 minutes andcollected by filtration over a sintered glass filter. Product was driedat high vacuum overnight at room temperature then for 30 min at 40° C.under vacuum to get title material (E12e, 10.58 g, 97% yield) as whitesolid.

¹H NMR δ (DMSO-d₆, 400 MHz): 1.32 (2H, m) 1.34 (3H, s), 1.98 (8H, m),2.79 (2H, m), 3.21 (3H, m), 3.25 (3H, s), 3.43 (2H, m), 3.56 (2H, m),3.68 (2H, m), 4.61 (1H, m), 7.59 (1H, d), 7.62 (1H, dd), 8.30 (1H, d),10.19 (1H, m).

MH⁺=414.1.

EXAMPLE 12f3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile4-methylbenzenesulfonate. (E12f)

p-Toluenesulfonic acid monohydrate (11 mg, 0.06 mmol) was added to asolution of3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilefree base (23 mg, 0.06 mmol) in DCM (0.5 mL):Et₂O (0.5 mL) at rt. Thereaction was stirred for 3 h before the addition of Et₂O (10 mL) whichcaused the precipitation of a white solid. The solid was isolated byfiltration, washing with Et₂O (2×) and EtOAc (2×) to give3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro1,3-benzoxazole-5-carbonitrile 4-methylbenzenesulfonate (E12f, 27 mg,74%) as a white solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.28-1.40 (5H, m), 1.60-1.70 (2H, m),1.96-2.06 (4H, m), 2.09-2.17 (2H, m), 2.29 (3H, s), 3.10-3.28 (6H, m),3.40-3.46 (2H, m), 3.52-3.59 (2 H, m), 3.66-3.75 (2H, m), 4.57 (1H, m),7.11 (2H, d, J 8.0), 7.47 (2H, d, J 8.0), 7.60 (1 H, d, J 8.3), 7.71(1H, dd, J 8.3 and 1.2), 7.84 (1H, d, J 1.2), 8.71 (1H, m). Note: 2 Hnot visible in NMR spectrum as obscured by solvent or water.

LCMS: [M+H]⁺414.

EXAMPLE 12g3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilemethanesulfonate. (E12 g)

Methanesulfonic acid (4 μl, 0.06 mmol) was added to a solution of3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilefree base (24 mg, 0.06 mmol) in DCM (1 mL) at rt. The reaction wasstirred for 30 min before the addition of Et₂O (10 mL) which caused theprecipitation of a white solid. The solid was isolated by filtration,washing with Et₂O (2×) and EtOAc (2×) to give3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilemethanesulfonate (E12g, 9.6 mg, 31% yield) as a white solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.27-1.41 (5H, m), 1.61-1.73 (2H, m),1.96-2.19 (6H, m), 2.30 (3H, s), 3.11-3.29 (6H, m), 3.53-3.59 (2H, m),3.67-3.76 (2H, m), 4.57 (1H, m), 7.60 (1H, d, J 8.2), 7.71 (1H, d, J8.2), 7.86 (1H, s), 8.80 (1H, m). Note: 4H not visible in NMR spectrumas obscured by solvent or water.

LCMS: [M+H]⁺ 414.

EXAMPLE 133-[1-(cis-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilehydrochloride. (E13)

Diisopropylethylamine (0.02 mL, 0.115 mmol) was added to a solution of4-hydroxy-3-{[1-(cis-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile(D37, 22.6 mg, 0.058 mmol) in dichloromethane (2.5 mL) at rt underargon. The reaction was cooled to 0° C. and the triphosgene (9 mg, 0.03mmol) was added. The mixture was stirred for 30 min at 0° C. Thereaction was quenched with saturated aqueous NaHCO₃ (5 mL) andpartitioned between dichloromethane and water. The aqueous layer wasextracted with dichloromethane (2×) and the combined organics were dried(Na₂SO₄) and concentrated by rotary evaporation to give a pale yellowsolid. The residue was purified via chromatography (silica,dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) togive the free base of the title compound as a pale yellow solid. HCl(0.1 mL, 0.1 mmol, 1 M in diethyl ether) was added to a solution of thefree base in dichloromethane (0.5 mL) and the solvent removed by rotaryevaporation. The resulting residue was triturated with diethyl ether(2×) to give3-[1-(cis-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilehydrochloride (E13, 14.8 mg, 53.6% yield) as a pale yellow solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.33 (3H, s), 1.52-1.63 (2H, m), 1.75 (2H,m), 1.82-1.96 (4H, m), 2.09 (2H, m), 2.65 (2H, m), 3.16 (2H, m), 3.27(3H, s), 3.43-3.58 (5H, m), 3.71 (2H, m), 4.60 (1H, m), 7.60 (1H, d, J8), 7.71 (1H, dd, J 8 and 1.2), 8.37 (1H, d, J 1.2), 9.30 (1H, m).

M+H⁺ 414.

EXAMPLE 146-Methyl-1-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-dihydro-2H-indol-2-onehydrochloride. (E14)

A stirred solution of bis(1,1-dimethylethyl)[4-methyl-2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)phenyl]propanedioate(D40, 340 mg, 0.61 mmol) in toluene (12 mL) at room temperature underargon was treated with 4-toluenesulphonic acid monohydrate (150 mg, 0.80mmol) and then heated at 110° C. for 2 hours. The mixture was allowed tocool, concentrated under vacuum and the residue treated with 10% Na₂CO₃solution (15 mL) and extracted with ethyl acetate (2×15 mL). Thecombined extract was dried (Na₂SO₄) and concentrated under vacuum. Theresidue was initially purified by chromatography on silica gel (20 g)eluting with 0-8% MeOH/dichloromethane, followed by purification usingmass-directed HPLC to afford the free base of the title compound as acolourless oil (170 mg). This material was dissolved in dichloromethane(2 mL), treated with 1M HCl/Et₂O (0.5 mL) and concentrated to afford thetitle compound E14 as a white solid (145 mg).

¹H NMR HCl salt δ (DMSO-d₆, 400 MHz): 0.88 (3H, t), 1.25-1.40 (2H, m+3H,s), 1.44-1.55 (2H, m), 1.80 (2H, br d), 1.90-2.10 (6H, br m), 2.33 (3H,s), 2.88-3.00 (2H, m), 3.10-3.26 (3H, m), 3.39 (2H, t), 3.50 (2H, s),3.63 (2H, br d), 4.53-4.63 (1H, m), 6.81 (1H, d), 7.12 (1H, d), 7.59(1H, s), 10.36 (1H, br s).

MH⁺=385.

EXAMPLE 153-{1-[trans-4-Ethoxy-1-methylcyclohexyl]-4-piperidinyl}-7-fluoro-5-methyl-1,3-benzoxazol-2(3H)-onehydrochloride. (E15)

To2-({1-[trans-4-ethoxy-1-methylcyclohexyl]-4-piperidinyl}amino)-6-fluoro-4-methylphenol(100 mg, 0.274 mmol) (D43) in dichloromethane (5 mL) at 0° C. were addeddiisopropylethylamine (0.15 mL, 0.859 mmol) and triphosgene (35 mg,0.118 mmol). After 30 min at 0° C. and 30 min at room temperature, themixture was washed with aqueous sodium bicarbonate, dried, andevaporated. Chromatography on silica (5 g), eluting with 0-10% 2Mammonia in methanol-dichloromethane, and conversion to the hydrochloridegave3-{1-[trans-4-ethoxy-1-methylcyclohexyl]-4-piperidinyl}-7-fluoro-5-methyl-1,3-benzoxazol-2(3H)-one(E15, 48 mg, 0.112 mmol, 41.0% yield) as the hydrochloride salt.

¹H NMR (HCl salt) δ (DMSO-d₆): 1.1 (3H, t), 1.35 (5H, m), 2.0 (8H, m),2.35 (3H, s), 2.8 (2H, b q), 3.2 (3H, m), 3.4 (2H, q), 3.7 (2H, m), 4.6(1H, m), 6.9 (1H, d), 7.6 (1H, s), 10.3 (1H, br s).

MH⁺ 391.

EXAMPLE 163-{1-[TRANS-4-ETHOXY-1-METHYLCYCLOHEXYL]-4-PIPERIDINYL}-6,7-DIFLUORO-5-methyl-1,3-benzoxazol-2(3H)-onehydrochloride. (E16)

To6-({1-[trans-4-ethoxy-1-methylcyclohexyl]-4-piperidinyl}amino)-2,3-difluoro-4-methyl-phenol(110 mg, 0.288 mmol) (D46) in dichloromethane (5 mL) at 0° C. were addeddiisopropylethylamine (0.15 mL, 0.859 mmol) and triphosgene (35 mg,0.118 mmol). After 30 min at 0° C. and 30 min at room temperature, themixture was washed with aqueous sodium bicarbonate, dried, andevaporated. Chromatography on silica (5 g), eluting with 0-5% 2M ammoniain methanol-dichloromethane, and conversion to the hydrochloride, gave3-{1-[trans-4-ethoxy-1-methylcyclohexyl]-4-piperidinyl}-6,7-difluoro-5-methyl-1,3-benzoxazol-2(3H)-one(E16, 62 mg, 0.132 mmol, 46.0% yield) as the hydrochloride salt.

¹H NMR (HCl salt) δ (DMSO-d₆): 1.1 (3H, t), 1.35 (5H, m), 2.0 (8H, m),2.3 (3H, s), 2.85 (2H, b q), 3.2 (3H, m), 3.4 (2H, q), 3.7 (2H, m), 4.6(1H, m), 7.8 (1H, d), 10.45 (1H, br s).

MH⁺ 409.

EXAMPLE 175-Methyl-3-{1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-onehydrochloride. (E17)

4-Methyl-2-({1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}amino)phenol(D48, 174 mg) was taken up in dry DCM (5.0 mL) containingdiisopropylethylamine (133 μl) and treated with triphosgene (120 mg).After two hours the reaction mixture was partitioned between DCM andNaHCO₃ (sat^(d) aq), the organic layers separated, dried over MgSO₄,filtered and the solvent removed under reduced pressure to afford awhite solid. Recrystallisation from ethanol afforded the title compound(E17, 72 mg).

¹H NMR δ (d₄-MeOH): 1.48 (4H m), 2.19 (2H, m), 2.67 (6H, m), 2.76 (3H,s), 3.15 (2H, m), 3.26 (4H, m), 3.32 (3H,s), 3.83 (2H, m), 4.48 (1H, m),6.99 (1H, dd, J=8.0 and 0.8 Hz), 7.07 (1H, d, J=8.0 Hz), 7.31 (1H, s).

(M+H)⁺ 359.

EXAMPLE 183-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5,7-difluoro-1,3-benzoxazol-2(3H)-onehydrochloride. (E18)

2-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4,6-difluorophenol(D49; assumed 0.530 mmol crude) was dissolved in dichloromethane (3 mL)and diisopropylethylamine (203 μl) was added, followed by triphosgene(173 mg, 0.583 mmol) in dichloromethane (2 mL). The reaction mixture wasstirred at room temperature for 5 h. The reaction mixture was treatedwith aqueous saturated sodium bicarbonate (5 mL) and stirred for 10 min.The layers were separated via phase separator and the organic layerevaporated to give a brown oil. This was purified by mass-directed LC/MSin 2 batches. The fractions containing product were treated with 2Mammonia in methanol (1 mL) then evaporated thoroughly. Both fractionswhen evaporated gave white-yellow solids. These were dissolved inmethanol and loaded onto SCX-3 cartridges (1 g). The cartridges wereeluted with methanol (6 mL each), followed by 0.5 M ammonia in methanol(8 mL each). The basic eluants were combined and evaporated to drynessto give a yellow solid. This material was obtained as an HCl salt bydissolving in 4.0M HCl in 1,4-dioxane, stirring for 20 min, thenevaporating to dryness to give the title compound E18 as a yellow solid(17 mg, 7.5%).

¹H NMR (HCl salt) δ (DMSO-d₆, 400 MHz): 1.08 (3H, t, J=8.6 Hz), 1.35(2H, br. s), 1.87-2.06 (8H, br. m), 2.75-2.84 (2H, br. s), 3.19 (3H, br.s), 3.47 (2H, q, J=6.8 Hz), 3.65-3.73 (4H, br. m), 4.15 (1H, br. m),4.646 (1H, br. m), 7.20 (1H, m), 7.76 (1H, m), 10.35 (1H, br. s).

(M+H)⁺=395.

EXAMPLE 193-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-[(trifluoromethyl)oxy]-1,3-benzoxazol-2(3H)-onehydrochloride. (E19)

2-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-[(trifluoromethyl)oxy]phenol (D50, 90 mg, 0.216 mmol) was dissolved in anhydrousdichloromethane (DCM) (3 mL) and diisopropylethylamine (0.075 mL, 0.432mmol) was added. The reaction mixture was cooled to 0° C. andtriphosgene (25.7 mg, 0.086 mmol) was added. The reaction mixture wasstirred for 1 h. The reaction mixture was treated with saturated sodiumbicarbonate solution (4 mL) and diluted with DCM (7 mL) and water (6mL). The layers were separated. The organic layer was dried withmagnesium sulphate and evaporated to dryness. The residue was purifiedby mass-directed LC/MS (MDAP). Fraction 1 was deemed to be the only pureone, so this was basified with ammonia and evaporated to dryness. Theresidual salts were removed on an IST SCX-2 (5 g) cartridge, washingwith methanol (40 mL) and 0.5 M ammonia in methanol (40 mL). The basiceluant was evaporated to dryness to give a colourless oil. This wasredissolved in methanol (4 mL) and 2.0 M HCl in diethyl ether (4 mL).The solution was stirred for 15 min at room temperature and evaporatedto dryness to give the title compound (E19) as a tan solid (22 mg, 21%).

¹H NMR δ (d₄-MeOH, 400 MHz): 1.18 (3H, t, J=6.8 Hz), 1.41-1.49 (5H, br.m), 1.80-1.86 (2H, br. m), 2.11 (4H, m), 2.22 (2H, m), 2.75-2.84 (2H,br. m), 3.24-3.37 (3 h, br. m, obscured by methanol peak), 3.57 (2H, qmJ=6.8 Hz), 3.83 (2H, m), 4.41 (1H, m), 7.11 (1H, d, J=8.4 Hz), 7.34 (1H,d, J=8.8 Hz), 7.57 (1H, s).

(M+H)⁺=443. Rt 2.56

EXAMPLE 203-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5,6-difluoro-1,3-benzoxazol-2(3H)-onehydrochloride. (E20)

2-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4,5-difluorophenol(D51, 253 mg, 0.401 mmol) was dissolved in dichloromethane (DCM) (5 mL)and diisopropylethylamine (0.437 mL, 2.5 mmol) was added. The reactionmixture was cooled to 0° C. under argon and triphosgene (89 mg, 0.301mmol) was added. The reaction mixture was stirred for 1 h. The reactionmixture was treated with saturated sodium bicarbonate solution (4 mL),then diluted with DCM and water (6 mL) of each. The layers wereseparated and the organic layer dried (magnesium sulphate) andevaporated. The residue was purified by flash column chromatography,using an IST pre-packed silica cartridge (20 g) and a gradient of 100%DCM to 0.3% ammonia, 5.7% methanol, 94% DCM, giving the crude product asan orange oil. This was further purified by mass-directed LC/MS (MDAP).

Fraction 1 was neutralised and evaporated to dryness. The resultingsolid was purified on an IST SCX-2 cartridge (5 g), washing withmethanol (30 mL) and eluting with 0.5M ammonia in methanol (30 mL). Thebasic wash was evaporated to dryness.

Fraction 2 was neutralised with ammonia and evaporated to dryness. Theresulting solid was partitioned between dichloromethane and saturatedsodium bicarbonate solution (4 mL of each). The layers were separatedwith a phase separator, and the organic layer evaporated to dryness.

The products obtained from work-up of fractions 1 and 2 were combinedand evaporated to dryness. The resulting white solid was dissolved inDCM (1 mL) and 2.0 M HCl in diethyl ether was added (159 μl, 5 eq.). Thesolution was stirred for 30 min, then evaporated to dryness. Thematerial was re-evaporated from 1:1 DMSO-d⁶: methanol (after NMR wasunresolved), giving the title compound E20 as a white solid (22 mg,13%).

(M+H)⁺=395, Rt 2.36

¹H NMR (HCl salt) δ (DMSO-d_(s), 400 MHz): 1.10 (3H, t, J=6.8 Hz), 1.32(3H, br. s), 1.92-2.04 (8H, br. m), 2.83 (2H, m), 3.19 (3H, m), 3.34(2H, br. s), 3.47 (2H, m), 3.67 (2H, m), 4.57 (1H, m), 7.73 (1H, m),8.21 (1H, m), 10.5 (1H, br. s).

EXAMPLE 213-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-onehydrochloride. (E21)

2-({1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-(trifluoromethyl)phenol(D53, 225 mg, 0.406 mmol) was dissolved in dichloromethane (5 mL) anddiisopropylethylamine (0.248 mL, 1.419 mmol) was added. The reactionmixture was cooled to 0° C. under argon and triphosgene (90 mg, 0.304mmol) was added. The reaction mixture was stirred for 1 h. The reactionmixture was treated with saturated sodium bicarbonate solution (4 mL),then diluted with dichloromethane and water (6 mL) of each. The layerswere separated and the organic layer dried (magnesium sulphate) andevaporated.

The residue was purified by flash column chromatography on a Biotage SP4(12+M cartridge) using a dichloromethane to 0.5% ammonia/9.5%Methanol/90% dichloromethane gradient, to give a colourless oil.

The oil was purified by mass-directed LC/MS (MDAP). Fraction 1 wascollected, neutralised with ammonia and evaporated to dryness. Theresidue was purified on an IST SCX-2 cartridge (5 g), washing withmethanol (30 mL) and eluting with 0.5 M ammonia in methanol (30 mL). Thebasic wash was evaporated to dryness to give a white solid.

The solid was dissolved in dichloromethane (2 mL) and 2.0 M hydrogenchloride in diethyl ether (2 mL) was added. The solution was stirred for15 min, then evaporated thoroughly to give a white solid (43 mg). Thiswas re-evaporated from 1:2 DMSO-d⁶: ethanol (3 mL) giving the titlecompound (E21) as a white solid (37 mg, 20%).

(M+H)⁺=427.

¹H NMR (HCl salt) δ (DMSO-d₆, 400 MHz): 1.10 (3H, t, J=6.8 Hz), 1.33(3H, br. s), 1.90-2.08 (8H, br. m), 2.85 (2H, m) 3.19 (3H, m), 3.33 (2H,br. s), 3.47 (2H, q, J=6.8 Hz), 3.68 (2H, m), 4.63 (1H, m), 7.55 (2H,m), 8.17 (1H, s), 10.5 (1H, br. s).

EXAMPLE 226-Methyl-1-{1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}-1,3-dihydro-2H-indol-2-onehydrochloride. (E22)

bis(1,1-Dimethylethyl)[4-methyl-2-({1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}amino)phenyl]propanedioate(D54) (1 eq., 0.19 mmol, 100 mg), 4-methylbenzenesulfonic acidmonohydrate (1.3 eq., 0.24 mmol, 46 mg) were dissolved in toluene (4 mL)and heated at 120° C. for 2 hours. The mixture was then cooled to Rt,the solvent was evaporated and the crude was then partitioned betweenNa₂CO₃ (10% aq. solution) and EtOAc. The two phases were separated andthe aqueous phase was extracted with EtOAc (2×); organics were combined,dried (Na₂SO₄) and concentrated under vacuum to leave a beige solid,which was purified by silica chromatography (12M column, EtOAc-nhex) toafford the product as a free base, (50 mg, 74%). This was dissolved inMeOH (3 mL) and treated with a 1M solution (in Et₂O) of HCl (2 eq., 0.28mmol, 0.28 mL). The mixture was stirred at Rt for 5 min, the solvent wasevaporated and the solid obtained was triturated with Et₂O to afford thetitle compound E22, (47 mg, 89%).

H⁺=357.

¹H NMR (HCl salt) δ (d₆-DMSO, 400 MHz): 1.24-1.34 (5H, m), 1.79-2.02(8H, m), 2.34 (3H, s), 2.89 (2H, q), 3.06-3.21 (3H, m), 3.26 (3H, s),3.49 (2H, s), 3.64 (2H, d), 4.54 (1H, m), 6.82 (1H, d), 7.13 (1H, d),7.48 (1H, s), 10.1 (1H, s br).

EXAMPLE 233-{1-[trans-1-Methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilehydrochloride. (E23)

4-Hydroxy-3-({1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}amino)benzonitrile(D55, 200 mg, 0.582 mmol) was dissolved into dry dichloromethane (DCM)(4 mL) and DIPEA (0.135 mL, 0.757 mmol) was added at Rt followed bytriphosgene (69.1 mg, 0.233 mmol) at Rt. The mixture was stirred at Rtfor 2 hours. The mixture was quenched with saturated aqueous solution ofNaHCO₃, diluted with DCM (10 mL), stirred vigorously for 10 min and theorganic phase was separated from the aqueous by hydrophobic filter toafford the crude product, which was purified by chromatography (25Ssilica column, MeOH—NH₃-DCM) to afford the free base, a pale-yellowsolid, (60%). This was dissolved in a mixture of methanol (1 mL) anddichloromethane (DCM) (0.5 mL) and treated with hydrochloric acid (0.352mL, 0.352 mmol) at 25° C. The mixture was stirred at 25° C. for 10minutes and the solvent was then evaporated to afford the title compound3-{1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilehydrochloride (E23, 118 mg, 0.276 mmol, 78% yield) as a pale-yellowsolid that was triturated with Et₂O and filtered to afford the titlecompound.

MH⁺=370.

¹H NMR δ (d₆-DMSO, 250 MHz, T=349K): 1.36 (4H, m), 1.90-2.10 (6H, m),2.75-3.2 (m), 3.27 (3H, s), 3.69 (2H, d), 4.58 (1H, m), 7.50 (1H, d),7.60 (1H, dd), 8.22 (1H, s br), 10.1 (1H, s br).

EXAMPLE 241-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-1,3-dihydro-2H-indol-2-onehydrochloride. (E24)

bis(1,1-Dimethylethyl)[2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-methylphenyl]propanedioate(D56) (1 eq., 0.25 mmol, 134 mg), was dissolved in toluene (4 mL) and4-methylbenzenesulfonic acid monohydrate (1.3 eq., 0.320 mmol, 61 mg)was added and the mixture was heated at 120° C. for 2 hours. The mixturewas then cooled to Rt, the solvent was evaporated and the crude was thenpartitioned between Na₂CO₃ (10% aq. solution) and EtOAc. The two phaseswere separated and the aqueous was extracted with EtOAc (2×); organicswere combined, dried (Na₂SO₄) and concentrated under vacuum to leave abeige solid, which was purified by silica chromatography (12M column,EtOAc-nhex) to afford the product as a free base, (70 mg in 76% yield).This material was dissolved in MeOH/dichloromethane mixture and treatedwith a 1M solution (in Et₂O) of HCl (2 eq.). The mixture was stirred atRt for 10 min, the solvent was evaporated and the solid obtained wastriturated with Et₂O to afford the title compound E24, (64 mg, 79%yield).

MH⁺=371.

¹H NMR (HCl salt) δ (d₆-DMSO, 250 MHz): 1.10 (3H, m), 1.17-1.33 (4H, m),1.80-2.00 (7H, m), 2.34 (3H, s), 2.85 (2H, q), 3.18-3.51 (m), 4.52 (1H,m), 6.82 (1H, d), 7.13 (1H, d), 7.42 (1H, s), 9.9 (1H, s br).

EXAMPLE 253-{1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-onehydrochloride. (E25)

Diisopropylethylamine (0.03 mL, 0.172 mmol) was added to a solution of2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)-4-(methylsulfonyl)phenol(D57, 31.4 mg, 0.074 mmol) in dichloromethane (5 mL) at rt under argon.The reaction was cooled to 0° C. and the triphosgene (16 mg, 0.054 mmol)was added. The mixture was stirred for 1 h at 0° C. The reaction wasquenched with saturated aqueous NaHCO₃ (5 mL) and partitioned betweendichloromethane and water. The aqueous layer was extracted withdichloromethane (2×) and the combined organics were dried (Na₂SO₄) andconcentrated by rotary evaporation to give a pale yellow solid. Theresidue was purified via chromatography (silica, dichloromethane to 0.5%ammonia/9.5% methanol/90% dichloromethane) to give the free base of thetitle compound as a white solid. HCl (0.1 mL, 0.1 mmol, 1 M in diethylether) was added to a solution of the free base in dichloromethane (0.5mL). The solvent was removed by rotary evaporation and the residuetriturated with diethyl ether to give3-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-onehydrochloride E25 (23.2 mg, 0.045 mmol, 61% yield) as a cream solid.

MH⁺ 451.

¹H NMR δ (DMSO-d₆, 400 MHz) 0.87 (3H, t, J 7.2), 1.25-1.40 (5H, m),1.47-1.53 (2H, m), 1.78 (2H, m), 1.99 (4H, m), 2.12 (2H, m), 2.69 (2H,m), 3.12-3.28 (3H, m), 3.82 (2 H, q, J 7.2), 3.70 (2H, m), 4.64 (1H, m),7.63 (1H, d, J 8.6), 7.76 (1H, dd, J 8.6 and 1.6), 8.08 (1H, d, J 1.6),9.53 (1H, m).

EXAMPLE 261-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-7-methyl-3,4-dihydro-2(1H)-quinolinone.(E26)

A stirred solution of the crude3-[2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-methylphenyl]propanoicacid (D58, 75 mg, 0.186 mmol) in N,N-dimethylformamide (DMF) (3 mL)under argon was treated with EDC (39.3 mg, 0.205 mmol), HOBT (31.4 mg,0.205 mmol) and finally triethylamine (0.057 mL, 0.410 mmol) and theresulting solution stirred o/n at rt. The mixture was concentrated todryness under vacuum and the residue partitioned between 1:1 dilutepotassium carbonate solution and DCM (20 mL). The organic phase wasseparated washed with brine (5 mL), dried (MgSO₄) and concentrated todryness in vacuo. LC/MS indicated that the residue consisted of amixture of components including the putative product (45.45%). This wasthen subjected to silica gel chromatography using Biotage SP1 with a12+M cartridge and eluting with 0-10% MeOH in DCM over 15 CV. Fractionscontaining the desired product were concentrated to dryness in vacuo togive a colourless gum. After triturating the product in diethylether/isohexane a colourless solid was produced which was collected byfiltration and dried at 40° C. under vacuum (E26, 4 mg, 5.58%).

¹H NMR δ (CDCl₃, 400 MHz) 1.20 (3H, t), 1.38-1.73 (8H, m), 1.88 (3H, m),2.18 (2H, t), 2.36 (3H, s), 2.45-2.62 (5H, m), 2.76 (2H, m), 3.08 (2H,d), 3.42 (1H, m), 3.48 (2H, q), 3.76 (1H, m), 4.08 (1H, m), 6.80 (1H,d), 7.02 (2H, m).

LC/MS ES+1.94 (94.06%) 385 (MH⁺).

EXAMPLE 273,3,6-Trimethyl-1-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-dihydro-2H-indol-2-onehydrochloride. (E27)

6-Methyl-1-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-dihydro-2H-indol-2-onehydrochloride (E14, 46 mg, 0.11 mmol) was suspended in DMF (3 mL) underAr and cooled to 0° C. Sodium hydride (18 mg, 0.45 mmol, 60% wt.suspension in oil) was added and the reaction stirred for 20 min at 0°C. Methyl iodide (0.014 mL, 0.23 mmol) was then added and the reactionstirred for a further 1 h at 0° C. A further portion of sodium hydride(5 mg, 0.13 mmol, 60% wt. suspension in oil) and methyl iodide (6 μl,0.10 mmol) were added and stirring continued for 1 h. The reaction wasquenched by the addition of sat. NaHCO₃ (10 mL) and extracted with EtOAc(2×). The combined organics were washed sequentially with sat. NaCl, H₂Oand sat. NaCl, dried (Na₂SO₄) and concentrated by rotary evaporation togive a yellow/brown oil. The crude residue was purified via flash columnchromatography (silica, DCM to 0.5% NH₃/9.5% MeOH/90% DCM) to give abrown oil which was further purified by high pH MDAP to give the freebase of the title compound. HCl (50 μl, 0.05 mmol, 1 M in Et₂O) wasadded to a solution of the free base in methanol (0.5 mL) and thesolvent was then removed by rotary evaporation to give a solid which wastriturated with Et₂O (2×) to give3,3,6-trimethyl-1-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-dihydro-2H-indol-2-onehydrochloride (E27, 7.1 mg, 13%) as a cream solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 0.87 (3H, t, J 7.5), 1.19-1.40 (11H, m),1.43-1.54 (2H, m), 1.76-1.90 (4H, m), 1.93-2.05 (4H, m), 2.34 (3H, s),2.72-2.86 (2H, m), 3.12-3.26 (3 H, m), 3.60-3.69 (2H, m), 4.48 (1H, m),6.86 (1H, d, J 7.5), 7.22 (1H, d, J 7.5), 7.31 (1 H, s), 9.54 (1H, m).Note: 2H not visible in NMR spectrum as obscured by solvent or water.

LCMS: [M+H]⁺413.

EXAMPLE 286-Methyl-1-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-onehydrochloride. (E28)

p-Toluenesulfonic acid monohydrate (53 mg, 0.277 mmol) was added to asolution of bis(1,1-dimethylethyl)(4-methyl-2-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}phenyl)propanedioate(D81, 106 mg, 0.11 mmol) in toluene (10 mL) and the reaction was heatedto 120° C. for 2 h. The solvent was removed rotary evaporation and thecrude residue was partitioned between 10% Na₂CO₃ solution and EtOAc. Theaqueous layer was extracted with EtOAc (2×) and the combined organicswere dried (Na₂SO₄) and concentrated by rotary evaporation to give ayellow oil. The crude residue was purified by flash columnchromatography (silica, DCM to 0.5% NH₃/9.5% MeOH/90% DCM) to give thefree base of the title compound as a colourless oil. HCl (0.15 mL, 0.15mmol, 1 M in Et₂O) was added to a solution of the free base in DCM (5mL) and the reaction stirred for 1 h. The solvent removed by rotaryevaporation and the resulting solid triturated with Et₂O to give6-methyl-1-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-onehydrochloride (E28, 36 mg, 72%) as a pale yellow solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.27-1.38 (5H, m), 17.4-1.90 (4H, m),1.94-2.04 (4H, m), 2.34 (3H, s), 2.72-2.87 (2H, m), 3.11-3.27 (6H, m),3.39-3.45 (2H, m), 3.49 (2H, s), 3.52-3.58 (2H, m), 3.59-3.68 (2H, m),4.46 (1H, m), 6.83 (1H, d, J 7.4), 7.14 (1H, d, J 7.4), 7.24 (1H, s),9.39 (1H, m).

LCMS: [M+H]⁺401.

EXAMPLE 293-{1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-5-[(trifluoromethyl)sulfonyl]-1,3-benzoxazol-2(3H)-onehydrochloride. (E29)

Hunig's Base (0.02 mL, 0.12 mmol) was added to a solution of2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)-4-[(trifluoromethyl)sulfonyl]phenol(D84, 22 mg, 0.05 mmol) in DCM (3 mL) at rt under Ar. The reaction wascooled to 0° C. and the triphosgene (12 mg, 0.04 mmol) was added. Themixture was stirred for 2 h at 0° C. The reaction was quenched with sat.NaHCO₃ (5 mL) and partitioned between DCM and H₂O. The aqueous layer wasextracted with DCM (2×) and the combined organics were dried (Na₂SO₄)and concentrated by rotary evaporation to give a yellow oil. The residuewas purified via flash column chromatography (silica, DCM to 0.5%NH₃/9.5% MeOH/90% DCM) to give the free base of the title compound as acolourless oil. HCl (0.1 mL, 0.1 mmol, 1 M in Et₂O) was added to asolution of the free base in DCM (0.5 mL) and the solvent was removed byrotary evaporation. The resulting solid was triturated with Et₂O to give341-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-5-[(trifluoromethyl)sulfonyl]-1,3-benzoxazol-2(3H)-onehydrochloride (E29, 20 mg, 76%) as a cream solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 0.87 (3H, t, J 7.4), 1.27-1.40 (5H, m),1.44-1.54 (2H, m), 1.68-1.79 (2H, m), 1.94-2.04 (4H, m), 2.10-2.18 (2H,m), 2.54-2.66 (2H, m), 3.09-3.22 (3H, m), 3.38 (2H, t, J 6.6), 3.66-3.73(2H, m), 4.67 (1H, m), 7.81 (1H, d, J 8.5), 7.99 (1H, dd, J 8.5 and1.9), 8.11 (1H, d, J 1.9), 9.25 (1H, m).

LCMS: [M+H]⁺505.

EXAMPLE 306-Methyl-3-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-onehydrochloride. (E30)

Hunig's base (0.05 mL, 0.29 mmol) was added to a solution of5-methyl-2-({1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)-4-(methylsulfonyl)phenol(D88, 49 mg, 0.11 mmol) in DCM (3 mL) at rt under Ar. The reaction wascooled to 0° C. and triphosgene (22 mg, 0.07 mmol) was added. Themixture was stirred for 2 h at 0° C. The reaction was quenched with sat.NaHCO₃ (5 mL) and partitioned between DCM and H₂O. The aqueous layer wasextracted with DCM (2×) and the combined organics were dried (Na₂SO₄)and concentrated by rotary evaporation to give a yellow oil, which waspurified via flash column chromatography (silica, DCM to 0.5% NH₃/9.5%MeOH/90% DCM) to give the free base of the title compound as a creamsolid. HCl (0.16 mL, 0.16 mmol, 1 M in Et₂O) was added to a solution ofthe free base in DCM (0.5 mL) and the solvent was removed by rotaryevaporation. The resulting solid was triturated with Et₂O to give6-methyl-3-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-onehydrochloride (E30, 43 mg, 74%) as a cream solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 0.87 (3H, t, J 7.4), 1.26-1.40 (5H, m),1.43-1.54 (2H, m), 1.70-1.82 (2H, m), 1.93-2.04 (4H, m), 2.06-2.15 (2H,m), 2.55-2.70 (5H, m), 3.12-3.31 (6H, m), 3.38 (2H, t, J 6.6), 3.62-3.72(2H, m), 4.60 (1H, m), 7.53 (1H, s), 7.89 (1 H, s), 9.40 (1H, m).

LCMS: [M+H]⁺465.

EXAMPLE 316-Methyl-5-(methylsulfonyl)-3-{1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-onehydrochloride. (E31)

Hunig's base (0.01 mL, 0.06 mmol) was added to a solution of5-methyl-4-(methylsulfonyl)-2-({1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinyl}amino)phenol(D89, 14 mg, 0.03 mmol) in DCM (3 mL) at rt under Ar. The reaction wascooled to 0° C. and the triphosgene (5 mg, 0.02 mmol) was added. Themixture was stirred for 2 h at 0° C. The reaction was quenched with sat.NaHCO₃ (5 mL) and partitioned between DCM and H₂O. The aqueous layer wasextracted with DCM (2×) and the combined organics were dried (Na₂SO₄)and concentrated by rotary evaporation to give a yellow oil, which waspurified via flash column chromatography (silica, DCM to 0.5% NH₃/9.5%MeOH/90% DCM) to give the free base of the title compound as a paleyellow oil. HCl (0.1 mL, 0.1 mmol, 1 M in Et₂O) was added to a solutionof the free base in DCM (0.5 mL) and the solvent was removed by rotaryevaporation. The resulting solid was triturated with Et₂O to give6-methyl-5-(methylsulfonyl)-3-{1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-onehydrochloride (E31; 11 mg, 62%) as a cream solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 0.86 (3H, t, J 7.4), 1.14-1.26 (2H, m),1.43-1.59 (4H, m), 2.01-2.15 (6H, m), 2.67 (3H, s), 3.16-3.31 (7H, m),3.37 (2H, t, J 6.6), 3.49-3.57 (2 H, m), 4.57 (1H, m), 7.53 (1H, s),7.87 (1H, s), 9.63 (1H, m). Note: 2H not visible in

NMR spectrum as obscured by solvent.

LCMS: [M+H]⁺451.

EXAMPLE 325-Methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbonitrilehydrochloride. (E32)

Hunig's Base (0.06 mL, 0.34 mmol) was added to a solution of5-hydroxy-2-methyl-4-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile(D93, 62 mg, 0.16 mmol) in DCM (3 mL) at rt under Ar. The reaction wascooled to 0° C. and the triphosgene (21 mg, 0.07 mmol) was added. Themixture was stirred for 2 h at 0° C. The reaction was quenched with sat.NaHCO₃ (5 mL) and partitioned between DCM and H₂O. The aqueous layer wasextracted with DCM (2×) and the combined organics were dried (Na₂SO₄)and concentrated by rotary evaporation to give a yellow oil. The cruderesidues were purified via flash column chromatography (silica, DCM to0.5% NH₃/9.5% MeOH/90% DCM) to give the free base of the title compoundas a colourless oil. HCl (0.2 mL, 0.2 mmol, 1 M in Et₂O) was added to asolution of the free base in DCM (0.5 mL) and the solvent was removed byrotary evaporation. The resulting solid was triturated with Et₂O to give5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbonitrilehydrochloride (E32, 49 mg, 64%) as a beige solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.26-1.39 (5H, m), 1.82-1.93 (2H, m),1.94-2.10 (6H, m), 2.53 (3H, s), 2.72-2.85 (2H, m), 3.12-3.28 (6H, m),3.40-3.45 (2H, m), 3.53-3.58 (2 H, m), 3.62-3.72 (2H, m), 4.58 (1H, m),7.87 (1H, s), 7.99 (1H, s), 10.09 (1H, m).

LCMS: [M+H]⁺428.

EXAMPLE 335-(Difluoromethoxy)-3-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-onehydrochloride. (E33)

4-(Difluoromethoxy)-2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-phenol(D96, 118 mg, 0.296 mmol) was dissolved in DCM (5 mL) and DIPEA (0.052mL, 0.296 mmol) was added. The reaction mixture was cooled to 0° C.under argon and triphosgene (58.0 mg, 0.195 mmol) was added. Thereaction mixture was stirred for 1 h. The reaction mixture was treatedwith saturated sodium bicarbonate solution (4 mL), then diluted with DCMand water (6 mL of each). The layers were separated and the organiclayer dried (MgSO₄) and evaporated. The residue was purified by flashcolumn chromatography, using a pre-packed silica cartridge (10 g),eluting with 0-3% 0.2 M ammonia in methanol in DCM to afford the productas a colourless oil. This was converted to an HCl salt by treating with2 M HCl in diethyl ether, giving a white solid (E33, 45 mg).

(M+H)⁺=425.

¹H NMR δ (CD₃OD): 1.18 (3H, t, J=6.8 Hz), 1.43-1.48 (2H, m), 1.46 (3H,s), 1.86 (2H, m), 2.12 (4H, m), 2.21 (2H, m), 2.82 (2H, m), 3.25-3.34(3H, m), 3.57 (2H, q, J=6.8 Hz), 3.83 (2H, m), 4.55 (1H, m), 6.90 (1H,t, J=74.0 Hz), 6.96 (1H, d, J=8.4 Hz), 7.28 (1H, d, J=8.8 Hz), 7.41 (1H,s).

EXAMPLE 345-Methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-onehydrochloride. (E34)

4-Methyl-2-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-amino}phenol(D97, 56 mg, 0.149 mmol) was dissolved in DCM (3 mL) and DIPEA (0.052mL, 0.297 mmol) was added. The reaction mixture was cooled to 0° C. andtriphosgene (33 mg, 0.111 mmol) was added. The reaction mixture wasstirred for 1.5 h. LC/MS analysis showed the reaction to be incomplete.An additional 0.75 eq. of triphosgene (33 mg) was added and the reactionmixture stirred for 42 h. The reaction mixture was treated withsaturated sodium bicarbonate solution (2 mL) and stirred for 15 min. Thereaction mixture was diluted with DCM and water (6 mL of each) and thelayers separated using a phase separator cartridge. The organic layerwas evaporated to dryness to give a colourless oil. The crude productwas purified by flash column chromatography on a pre-packed silicacartridge (column size 10 g), eluting with 3-7% 2 M ammonia in methanolin DCM to afford the product as a colourless oil. This was treated with2 M HCl in diethyl ether to afford the HCl salt E34 as a white solid (38mg).

(M+H)⁺=403.

¹H NMR δ (CD₃OD): 1.43-1.51 (1H, m), 1.47 (3H, s), 1.83 (2H, m), 2.15(6H, m), 2.42 (3H, s), 2.80 (2H, m), 3.24-3.40 (7H, m), 3.53 (2H, m),3.65 (2H, m), 3.83 (2H, m), 4.51 (1H, m), 6.98 (1H, d, J=8.4 Hz), 7.13(1H, d, J=8.0 Hz), 7.33 (1H, s).

EXAMPLE 353-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(methyloxy)-1,3-benzoxazol-2(3H)-onehydrochloride. (E35)

2-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-(methyloxy)phenol(D98, 31 mg, 0.079 mmol) was dissolved in DCM (3 mL) and DIPEA (0.043mL, 0.246 mmol) was added. The reaction mixture was cooled to 0° C. andtriphosgene (37 mg, 0.125 mmol) was added. The reaction mixture wasstirred for 64 h, warming to room temperature. The reaction mixture wastreated with saturated sodium bicarbonate solution. The reaction mixturewas diluted with DCM and water (6 mL of each) and the layers separatedwith a phase separator cartridge. The organic layer was evaporated todryness. The crude product was purified by flash column chromatographyon a pre-packed silica cartridge (column size 10 g), eluting with 2-5%0.2 M ammonia in methanol in DCM to afford the desired product as acolourless oil. This was treated with 2 M HCl in diethyl ether to affordthe HCl salt E35 as a white solid (10 mg).

(M+H)⁺=419.

¹H NMR δ (CD₃OD): 1.45-1.48 (2H, m), 1.46 (3H, s), 1.89 (2H, m), 2.15(6H, m), 2.85 (2H, m), 3.29 (2H, m), 3.37 (4H, m), 3.52 (2H, m), 3.64(2H, m), 3.82 (1H, s), 3.85 (3H, s), 4.55 (1H, m), 6.70 (1H, m), 7.15(2H, m). Note: 1H not visible in NMR spectrum as obscured by solvent orwater.

EXAMPLE 363-(1-{trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexyl}-4-piperidinyl)-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-onehydrochloride. (E36)

2-[(1-{trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexyl}-4-piperidinyl)amino]-4-(methylsulfonyl)phenol(D106, 80 mg, 0.183 mmol) was suspended in DCM (5 mL) and DIPEA (0.065mL, 0.372 mmol) was added. The reaction mixture was cooled to 0° C. andtriphosgene (35.9 mg, 0.121 mmol) was added. The reaction mixture wasstirred at 0° C. for 1 h, then allowed to warm to room temperature. Thereaction mixture was treated with saturated sodium bicarbonate solution(4 mL) and stirred for 10 min. The reaction mixture was diluted with DCMand water (10 mL each) and the layers separated. The aqueous layer wasextracted with DCM (2×10 mL) and the combined organics were dried(MgSO₄) and evaporated. The crude product was purified by flash columnchromatography on a pre-packed silica cartridge (column size 10 g),eluting with 3-6% 0.2 M ammonia in methanol in DCM, to afford thedesired product as a colourless oil. This was treated with 2 M HCl indiethyl ether to afford the desired product E36 as an HCl salt (72 mg).

(M+H)⁺=463.

¹H NMR δ (CD₃OD): 0.21 (2H, m), 0.50 (2H, m), 1.02 (1H, m), 1.45 (5H,m), 1.85 (2H, m), 2.12 (4H, m), 2.25 (2H, m), 2.85 (2H, m), 3.21 (3H,s), 3.32 (5H, m), 3.85 (2H, m), 4.65 (1H, m), 7.50 (1H, d, J=8.4 Hz),7.81 (1H, m), 8.07 (1H, s).

EXAMPLE 373-(1-{trans-1-Methyl-4-[(1-methylethyl)oxy]cyclohexyl}-4-piperidinyl)-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-onehydrochloride. (E37)

2-[(1-{trans-1-methyl-4-[(1-methylethyl)oxy]cyclohexyl}-4-piperidinyl)amino]-4-(methylsulfonyl)phenol(D113, 125 mg, 0.247 mmol) was dissolved in DCM (5 mL) and DIPEA (0.151mL, 0.866 mmol) was added. The reaction mixture was cooled to 0° C.,then triphosgene (49 mg, 0.165 mmol) was added. The reaction mixture wasstirred at 0° C. for 1.5 h. The reaction mixture was treated withsaturated sodium bicarbonate solution (5 mL) and stirred for 10 min. Thereaction mixture was diluted with DCM and water (10 mL of each) and thelayers separated. The aqueous layer was extracted with DCM (2×10 mL).The combined organics were dried (MgSO₄) and evaporated. The crudeproduct was purified by flash column chromatography on a pre-packedsilica cartridge (column size 10 g), eluting with 3-6% (0.2 M ammonia inmethanol) in DCM to give a colourless oil. This was treated with 2 M HClin diethyl ether to afford the desired product E37 as an HCl salt (74mg).

(M+H)⁺=451.

¹H NMR δ (CD₃OD): 1.15 (6H, d, J=6.0 Hz), 1.46 (5H, m), 1.84 (2H, m),2.06 (4H, m), 2.25 (2H, m), 2.82 (2H, m), 3.20 (3H, s), 3.26 (1H, m),3.43 (1H, m), 3.81 (3H, m), 4.63 (1H, m), 7.50 (1H, m), 7.82 (1H, m),8.04 (1H, s). Note: 1H not visible in NMR spectrum as obscured bysolvent or water.

EXAMPLE 383-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-onehydrochloride. (E38)

2-{[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-(trifluoromethyl)phenol(D114, 109 mg, 0.253 mmol) was dissolved in dichloromethane (DCM) (5 mL)and cooled to 0° C. in an ice bath. DIPEA (0.15 mL, 0.859 mmol) wasadded followed by triphosgene (50 mg, 0.168 mmol). The reaction mixturewas left to stir for 30 min at 0° C. and 30 min at RT. The mixture waswashed with aqueous sodium bicarbonate, passed through a phaseseparation cartridge and evaporated to give a clear oil. Purified bycolumn (10 g) eluting with 0-10% 2M NH₃/MeOH/DCM to give a clear oil.Treated with 4M HCl in dioxan, evaporated to dryness to give a whitesolid3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-onehydrochloride (E38, 96.9 mg, 0.197 mmol, 78% yield).

¹H NMR δ (DMSO-d_(s), 400 MHz) 1.23-1.35 (5H, m), 1.87-2.08 (6H, m),2.79-2.88 (2H, m), 3.17-3.24 (5H, m), 3.32 (3H, s), 3.41-3.43 (2H, m),3.54-3.59 (2H, m), 3.66-3.73 (2H, m), 4.59-4.65 (1H, m), 7.52-7.68 (2H,m), 8.14 (1H, s), 10.4 (1H, m).

m/z (M+H)⁺ 457.

EXAMPLE 396-Fluoro-5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]-oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-onehydrochloride. (E39)

The title compound was prepared from the compound of Description 73 and2-amino-5-fluoro-4-methylphenol using the methods of Description 114 andExample 38.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.23-1.32 (5H, m), 1.82-2.02 (6H, m), 2.27(3H, s) 2.81-2.90 (2H, m), 3.15-3.24 (5H, m), 3.32 (3H, s), 3.40-3.43(2H, m), 3.53-3.59 (2H, m), 3.64-3.71 (2H, m), 4.52-4.58 (1H, m),7.34-7.36 (1H, d, J=8.0 Hz)), 7.96-7.97 (1H, d, J=4.0 Hz)), 10.5 (1H,m).

m/z (M+H)⁺421.

EXAMPLE 407-Fluoro-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilehydrochloride. (E40)

The title compound was prepared from the compound of Description 73 and3-amino-5-fluoro-4-hydroxybenzonitrile (see WO 2005074603 for synthesis)using the methods of Description 114 and Example 38.

¹H NMR δ (MeOH-d₄, 400 MHz) 0.87-0.96 (2H, m), 1.12-1.46 (6H, m),1.83-1.88 (2H, t) 2.12-2.15 (3H, m), 2.25-2.51 (2H, m), 2.76-2.85 (2H,m), 3.18-3.37 (6H, m), 3.51-3.56 (2H, m), 3.63-3.65 (2H, m), 4.57-4.67(1H, m), 7.51-7.42 (1H, d), 7.82 (1H, s).

m/z (M+H)⁺ 432.

EXAMPLE 417-Fluoro-5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-onehydrochloride. (E41)

The title compound was prepared from the compounds of Description 73 andDescription 116 using the methods of Description 114 and Example 38.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.25-1.36 (5H, m), 1.91-2.03 (6H, m), 2.35(3H, s) 2.81-2.90 (2H, m), 3.15-3.24 (5H, m), 3.32 (3H, s), 3.40-3.49(2H, m), 3.53-3.59 (2H, m), 3.64-3.71 (2H, m), 4.52-4.59 (1H, m),6.92-6.95 (1H, d), 7.70 (1H, s), 10.5 (1H, m).

m/z (M+H)⁺ 421.

EXAMPLE 426-Fluoro-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrilehydrochloride. (E42)

The title compound was prepared from the compound of Description 73 and5-amino-2-fluoro-4-hydroxybenzonitrile (D148) using the methods ofDescription 114 and Example 38.

¹H NMR δ (MeOH-d₄, 400 MHz) 1.39-1.50 (3H, m), 1.86-1.98 (2H, m),2.12-2.20 (3H, m), 2.23-2.34 (2H, m), 2.76-2.82 (2H, m), 3.24-3.36 (9H,m), 3.63-3.65 (2H, m), 3.82-3.85 (2H, m), 4.57-4.67 (1H, m), 7.43-7.45(1H, d), 7.91-7.93 (1H, m).

m/z (M+H)⁺ 432.

EXAMPLE 433-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-onehydrochloride. (E43)

The title compound was prepared from the compound of Description 73 and2-amino-4-(methylsulfonyl)phenol using the methods of Description 114and Example 38.

¹H NMR δ (MeOH-d₄, 400 MHz) 1.5 (2H, m), 1.75 (2H, m), 2.2 (4H, m), 2.25(2H, m), 2.75 (2H, m), 3.15 (3H, s), 3.3 (6H, s and m, obscured by MeOHpeak), 3.4 (3H, s), 3.55 (2H, m), 3.65 (2H, m), 3.85 (2H, m), 4.6 (1H,m), 7.5 (1H, d J=6.0 Hz), 7.8 (1H, d J=6.0 Hz), 7.95 (1H, s).

m/z (M+H)⁺ 467.

EXAMPLE 443-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-[(methyloxy)methyl]-1,3-benzoxazol-2(3H)-onehydrochloride. (E44)

To a stirred mixture of2-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-[(methyloxy)methyl]phenolD121 (58 mg, 0.143 mmol), and DIPEA (0.050 mL, 0.285 mmol) indichloromethane (DCM) (5 mL) cooled to 0° C. under argon was added, inportions, triphosgene (16.93 mg, 0.057 mmol). After stirring at 0° C.for 1 hr the reaction was quenched with dilute aq potassium bicarbonate(5 mL). The organic phase was separated, dried (MgSO₄) and concentratedto dryness in vacuo. The reside was subjected to silica gelchromatography using a Biotage Horizon with a 12+M cartridge and elutingwith 0-10% MeOH/DCM over 12 CVs. The product 53 mg, was isolated as athick colourless oil, which was dissolved in dichloromethane (DCM) (5mL) and treated with 1M HCl (0.2 mL) after stirring for 20 mins themixture was concentrated to dryness under vacuum and the residuetriturated in diethyl ether to afford the title compound E44 as acolourless solid 44 mg, 65.8%.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.33 (3H, m), 1.79-2.05 (8H, m), 2.87 (2H,q), 3.11-3.23 (5H, m), 3.25 (3H, s), 3.29 (3H, s), 3.41 (2H, m),3.50-3.67 (5H, m), 4.43 (1H, s), 4.55 (1H, t), 7.10 (1H, d), 7.31 (1H,d), 7.86 (1H, s), 10.28 (1H, m).

M+H⁺ 433.

EXAMPLE 45a1-[1-(trans-1-Methyl-4-[2-(methoxyethoxy)cyclohexyl]-4-piperidinyl]-6-(methoxymethyl)-1,3-dihydro-2H-indol-2-one.(E45a)

A mixture of bis(1,1-dimethylethyl){2-amino-4-[(methyloxy)methyl]phenyl} propanedioate (D124) (100 mg,0.285 mmol),1-(trans-1-methyl-4-[2-(methoxyethoxy)cyclohexyl]-4-piperidinone (D73)(100 mg, 0.371 mmol), acetic acid (0.2 mL, 3.49 mmol), dichloromethane(2.5 mL), and polymer supported cyanoborohydride (100 mg, 0.410 mmol)was heated to 110° C. for 45 min in the microwave. Filtration andevaporation gave crude product which was purified by MDAP to give1-[1-(trans-1-methyl-4-(2-(methoxyethoxy)cyclohexyl]-4-piperidinyl}-6-(methoxymethyl)-1,3-dihydro-2H-indol-2-one(E45a, 8 mg, 0.019 mmol, 6.53% yield) free base as a colourless oil.

¹H NMR δ (CDCl₃, 400 MHz, free base) 0.9 (3H, s), 1.5 (4H, m), 1.7 (7H,m), 1.9 (2H, m), 2.2 (2H, t), 2.4 (2H, q), 3.1 (2H, d), 3.4 (6H, 2s),3.5 (2H, s), 3.6 (2H, ABq), 4.2 (1 H, m), 4.5 (2H, s), 6.9 (1H, d), 7.1(1H, s), and 7.2 (1H, s).

[M+H]⁺ 430.

EXAMPLE 45b1-[1-(trans-1-Methyl-4-[2-(methoxyethoxy)cyclohexyl]-4-piperidinyl]-6-(methoxymethyl)-1,3-dihydro-2H-indol-2-onehydrochloride. (E45b)

A mixture of di t-butyl {2-amino-4-(methoxymethyl)phenyl}malonate (250mg, 0.711 mmol) (D124),1-(trans-1-methyl-4-{[2-(methoxyethoxy}cyclohexyl)-4-piperidinone (150mg, 0.557 mmol) (D73), acetic acid (0.2 mL, 3.49 mmol), dichloromethane(2.5 mL), and polymer supported cyanoborohydride (150 mg, 0.615 mmol)was heated to 100° C. for 1 h in the microwave. Filtration, evaporation,purification by MDAP, and conversion to the hydrochloride salt gave1-[1-(trans-1-methyl-4-[(2-(methoxyethoxy)cyclohexyl]-4-piperidinyl]-6-(methoxymethyl)-1,3-dihydro-2H-indol-2-onehydrochloride (E45b, 19 mg, 0.039 mmol, 6.94% yield) as a beige powderfrom diethyl ether.

¹H NMR δ (DMSO-d₆, 400 MHz, HCl salt) 1.4 (8H, m), 1.7 (2H, t), 1.8 (2H,d), 2.0 (4H, m), 2.7 (2H, q), 3.2-3.6 (14H, m), 4.4 (3H, m), 6.9 (1H,d), 7.2 (1H, d), 7.3 (1H, s), and 9.4 (1H, bs).

[M+H]⁺ 430.

EXAMPLE 463-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carboxamidehydrochloride. (E46)

To a stirred mixture of3-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-4-hydroxybenzamideD127 (48 mg, 0.128 mmol), and DIPEA (0.045 mL, 0.256 mmol) indichloromethane (DCM) (5 mL) cooled to room temp under argon was added,in small portions, triphosgene (15.17 mg, 0.051 mmol). After stirringfor 1 hr the reaction was quenched with dilute aq potassium bicarbonate(5 mL). The organic phase was separated, dried (MgSO₄) and concentratedto dryness in vacuo. The reside was subjected to silica gelchromatography using a Biotage Horizon with a 12+M cartridge and elutingwith 0-10% MeOH/DCM over 12 CVs. The product was isolated as a thickcolourless oil and was dissolved in dichloromethane (DCM) (5 mL) andtreated with 1M HCl (0.2 mL) after stirring for 20 mins the mixture wasconcentrated to dryness under vacuum and the residue triturated indiethyl ether to give the title compound E46 as colourless solid (34 mg,57.7%).

¹H NMR δ (DMSO-d_(s), 400 MHz) 1.09 (3H, t, J=6.8 Hz), 1.28-1.34 (6H,m), 1.89-2.09 (9H, m), 2.98 (2H, q), 3.12-3.27 (3H, m), 3.46 (2H, q),4.64 (1H, m), 7.43 (1H, d, J=6.8 Hz), 7.53 (1H, s), 7.79 (1H, d, J=6.8Hz), 8.17 (1H, s), 8.49 (1H, s), 10.14 (1H, m).

LC/MS 402 (MH+).

EXAMPLE 473-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carboxamidehydrochloride. (E47)

To a stirred mixture of4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]-oxy}cyclohexyl)-4-piperidinyl]amino}benzamideD128 (27 mg, 0.061 mmol), and DIPEA (0.021 mL, 0.122 mmol) indichloromethane (DCM) (5 mL) at room temp under argon was added, insmall portions, triphosgene (7.25 mg, 0.024 mmol). After stirring for 1hr the reaction was quenched with dilute aq potassium bicarbonate (5mL). The organic phase was separated, dried (MgSO₄) and concentrated todryness in vacuo. The reside was subjected to silica gel chromatographyusing a Biotage Horizon with a 12+M cartridge and eluting with 0-10%MeOH/DCM over 12 CVs. The product was isolated as a thick colourless oilwhich was dissolved in dichloromethane (DCM) (5 mL) and treated with 1MHCl (0.2 mL) after stirring for 20 mins the mixture was concentrated todryness under vacuum and the residue triturated in diethyl ether to givethe title compound E47 as a colourless solid (17 mg, 56.5%).

¹H NMR δ (DMSO-d₆, 400 MHz) 1.24-1.34 (6H, m), 1.87-2.09 (9H, m), 2.87(2H, q), 3.25 (5H, m), 3.55 (2H, m), 3.70 (3H, m), 4.64 (1H, m), 7.43(1H, d, J=6.8 Hz), 7.53 (1H, s), 7.79 (1H, d, J=6.8 Hz), 8.16 (1H, s),8.46 (1H, s), 10.08 (1H, m).

LC/MS 402 (MH⁺).

EXAMPLE 485-Acetyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-onehydrochloride. (E48)

To a stirred solution of1-(4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}phenyl)ethanoneD131 (30 mg, 0.074 mmol) and DIPEA (0.026 mL, 0.148 mmol) indichloromethane (DCM) (3 mL) at 0° C. under argon was slowly addedtriphosgene (8.80 mg, 0.030 mmol). After stirring at 0° C. for 20 minsthe mixture was allowed to warm to rt. After 2 hr the mixture was washedwith dilute aq. potassium carbonate solution (4 mL), dried andevaporated to dryness in vacuo. The residue was purified by MDAP whichafforded the free base as a colourless gum, after a basic work up. Thiswas dissolved in DCM (1 mL) and 1M HCl in diethyl ether (0.2 mL), afterstirring for 20 mins the mixture was concentrated to dryness undervacuum to yield the title compound E48 as a cream powder (8 mg, 21.95%).

¹H NMR δ (CDCl₃, 400 MHz) (free base) 1.47-1.58 (4H, m), 1.64-1.69 (5H,m) 1.86-1.92 (4H, m), 2.21-2.38 (4H, m), 2.63 (3H, s), 3.17 (2H, d),3.41 (3H, s), 3.46 (1H, m), 3.52-3.82 (4H, m), 4.11 (1H, s), 7.24 (1H,d), 7.74 (1H, d), 7.81 (1H, s).

LC/MS 431 (MH+).

EXAMPLE 493-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5[N-(methyloxy)ethanimidoyl]-1,3-benzoxazol-2(3H)-onehydrochloride. (E49)

To a stirred solution of1-(4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}-cyclohexyl)-4-piperidinyl]amino}phenyl)ethanoneO-methyloxime (D133) (40 mg, 0.092 mmol) and triethylamine (0.019 mL,0.138 mmol) in dichloromethane (DCM) (3 mL) cooled to 0° C. was slowlyadded triphosgene (10.95 mg, 0.037 mmol). After stirring at 0° C. for 15mins the cooling bath was removed and the mixture allowed to reach rtand was stirred for another 2 hr. The mixture was washed with dilute aqpotassium carbonate solution and brine, dried (MgSO₄) concentrated todryness under vacuum. The residue was subjected to silica gelchromatography using a Biotage Horizon with a 12+M column eluting with0-5% MeOH in DCM. A pale yellow solid was isolated, which was dissolvedin DCM (3 mL) and treated with 1M HCl (0.1 mL) in diethyl ether, afterstirring for 30 mins the mixture was concentrated to dryness undervacuum and the residue triturated in diethyl ether to afford the titlecompound E49 as a pale yellow solid (9 mg, 17.70%).

¹H NMR δ (DMSO-d₆, 400 MHz) 1.27-1.33 (5H, m), 1.88-2.07 (8H, m), 2.28(3H, s), 2.86 (2H, m), 3.19-3.24 (6H, m), 3.41 (2H, m), 3.55 (2H, m),3.65 (2H, d), 3.92 (3H, s), 4.59 (1H, m), 7.36 (1H, d), 7.43 (1H, d),7.91 (1H, s), 10.31 (1H, br s).

LC/MS 460 (MH+).

EXAMPLES 50 AND 511-[1-(trans-4-{2-Methoxyethoxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile.(E50) and1-[1-(cis-4-{2-Methoxyethoxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile.(E51)

A mixture of 4-(6-cyano-2-oxo-2,3-dihydro-1H-indol-1-yl)piperidinehydrochloride (200 mg, 0.829 mmol) (D137),4-(2-methoxyethoxy)cyclohexanone (200 mg, 1.161 mmol) (D61), polymersupported cyanoborohydride (300 mg, 1.230 mmol), acetic acid (0.2 mL,3.50 mmol), and dichloromethane (5 mL) was heated in the microwavereactor at 100° C. for 15 min, then filtered and evaporated.Purification by high pH MDAP gave the faster running isomer E50,1-[1-(trans-4-{2-methoxyethoxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile(30 mg, 0.075 mmol, 9.10% yield) free base, crystallised from diethylether, and then the slower running isomer E51,1-O-(cis-4-{2-methoxyethoxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile(45 mg, 0.113 mmol, 13.66% yield) free base, as a white foam.

trans isomer E50: [M+H]⁺ 398; Rt 2.37

¹H NMR δ (MeOH-d₄, 250 MHz, free base) 1.3 (4H, m), 1.7 (2H, bs), 2.0(2H, d), 2.2 (2 H, d), 2.5 (5H, m), 3.1 (2H, d), 3.3-3.6 (10H, m), 4.3(1H, m), 7.4 (2H, ABq), and 7.8 (1 H, s).

cis isomer E51: [M+H]⁺ 398; Rt 2.45

¹H NMR δ (MeOH-d₄, 400 MHz, free base) 1.4 (2H, m), 1.7 (6H, m), 2.0(2H, d), 2.5 (5 H, m), 3.2 (2H, d), 3.4 (3H, s), 3.6 (5H, m), 4.3 (1H,m), 7.4 (2H, ABq), and 7.8 (1H, s).

Note: 2H not visible in NMR spectrum as obscured by solvent or water.

EXAMPLE 523-{1-[trans-4-(Ethyloxy)cyclohexyl]-4-piperidinyl}-5-fluoro-1,3-benzoxazol-2(3H)-one.(E52)

A mixture of 5-fluoro-3-(4-piperidinyl)-1,3-benzoxazol-2(3H)-onehydrochloride D138 (0.2 g), 4-(ethyloxy)cyclohexanone (WO2007107566)(0.2 g), and Hunig's base (0.1 g) in N-methylpyrrolidone (5 mL) wasstirred for 2 hours then treated with sodium triacetoxyborohydride (0.5g) was added and stirring was continued for four days. The mixture wasdiluted with methanol, loaded onto a SCX column and the column waseluted with methanol followed by 2M ammonia in methanol. The methanolicammonia fractions were evaporated and the residue was purified by highpH MDAP. Two peaks were collected and evaporated separately. The fasteluting isomer gave3-{1-[trans-4-(ethyloxy)cyclohexyl]-4-piperidinyl}-5-fluoro-1,3-benzoxazol-2(3H)-oneE52 as a white solid (7 mg).

¹H NMR (CDCl₃) δ: 1.20 (3H, t), 1.25-1.4 (4H, m), 1.6 (2H, m), 1.88 (4H,m), 2.12 (2H, m) 2.22-2.42 (4H, m), 3.05 (2H, m), 3.20 (1H, m), 3.51(2H, t), 4.16 (1H, m), 6.87 (1H, m), 6.99 (1H, m), 7.17 (1H, m).

Mass Spectrum (LC/MS): Found 363 (MH⁺). Ret. time 1.92 min.

EXAMPLE 533-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-methyl[1,3]oxazolo[4,5-b]pyridin-2(3H)-onehydrochloride. (E53)

Hunig's Base (0.074 mL, 0.43 mmol) was added to a solution of2-({1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}amino)-6-methyl-3-pyridinolD146 (82 mg, 0.21 mmol) in DCM (5 mL) at rt under Ar. The reaction wascooled to 0° C. and the triphosgene (26 mg, 0.09 mmol) was added. Themixture was stirred for 50 min at 0° C. and then the reaction wasquenched with sat. NaHCO₃ (5 mL) and partitioned between DCM and H₂O.The aqueous layer was extracted with DCM (2×) and the combined organicswere dried (Na₂SO₄) and concentrated by rotary evaporation to give apale yellow solid. The crude residue was purified via Biotage (silica;DCM to 0.5% NH₃/9.5% MeOH/90% DCM; 12+M column) to give a residue whichwas further purified by high pH MDAP to give the free base of the titlecompound as a white solid. HCl (0.04 mL, 0.04 mmol, 1 M in Et₂O) wasadded to a solution of the free base in DCM (0.5 mL). The solvent wasremoved by rotary evaporation and the crude residue triturated with Et₂Oto give3-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-methyl[1,3]oxazolo[4,5-b]pyridin-2(3H)-onehydrochloride (E53) (4 mg, 4%) as a white solid.

¹H NMR (DMSO-d₆) δ: 1.10 (3H, t, J 7.0), 1.23-1.37 (5H, m), 1.68-1.79(2H, m), 1.90-2.03 (4H, m), 2.06-2.15 (2H, m), 2.48 (s, integrationobscured by solvent peak), 2.64-2.77 (2H, m), 3.12-3.30 (3H, m), 3.47(2H, q, J 7.0), 3.61-3.69 (2H, m), 4.61 (1H, m), 7.04 (1H, d, J 8.1),7.62 (1H, d, J 8.1), 8.95 (1H, m).

[M+H]⁺ 374.

The compounds3-{1-[cis-4-(Ethyloxy)cyclohexyl]-4-piperidinyl}-5-fluoro-1,3-benzoxazol-2(3H)-oneand5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-4-carbonitrilehydrochloride can be made in a similar manner to the Examples above.3-{1-[cis-4-(Ethyloxy)cyclohexyl]-4-piperidinyl}-5-fluoro-1,3-benzoxazol-2(3H)-oneand5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-4-carbonitrilehydrochloride were either not tested for activity or activity wasundetectable within the limits of the assays used (below the thresholdof detectability).

1. A method of treating a psychotic disorder, which method comprisesadministering to a mammal in need thereof an effective amount of acompound of formula (I) or a salt thereof:

wherein R⁴, R⁵ and R⁶ are independently selected from hydrogen, halogen,C₁₋₆alkyl, C₁₋₆alkyl substituted with one or more fluorine atoms, cyano,C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfonyl substituted with one or morefluorine atoms, C₃₋₆cycloalkyl, C₁₋₆alkoxy, C₁₋₆alkoxy substituted withone or more fluorine atoms, C₁₋₆alkanoyl, —C(═NOC₁₋₆alkyl)C₁₋₆alkyl,—C₁₋₆alkoxyC₁₋₆alkyl, and —C(O)NR_(a)R_(b); R_(a) and R_(b) are eachindependently H or C₁₋₆ alkyl, or together with the nitrogen atom towhich they are attached form a five or six membered ring; ring Arepresents a benzene ring, or a 6-membered aromatic heterocylic ringcontaining one or two nitrogen atoms; R is selected from C₁₋₆alkyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₄alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₃₋₆cycloalkyloxyC₁₋₆alkyl and C₃₋₆cycloalkylC₁₋₄alkyloxyC₁₋₆alkyl,wherein any alkyl or cycloalkyl group is optionally substituted by oneor more fluorine atoms; Q is selected from hydrogen and C₁₋₆alkyl; and Yis selected from O, S, CH₂ optionally substituted with one or twofluorine atoms or optionally substituted with one or two methyl groups,CH₂CH₂, OCH₂, and CH₂O.
 2. A method as claimed in claim 1 wherein R⁶ iscyano.
 3. A method as claimed in claim 1 wherein R isC₃₋₆cycloalkylC₁₋₄alkyl.
 4. A method as claimed in claim 1 wherein Y isO.
 5. A method as claimed in claim 1 wherein A is a benzene ring.
 6. Amethod as claimed in claim 1 wherein the compound is selected from thegroup consisting of:3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one;3-{1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one;3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-pipendinyl}-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidlinyl}-6-fluoro-5-methyl-1,3-benzoxazol-2(3H)-one;3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidlinyl}-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one;3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(ethylsulfonyl)-1,3-benzoxazol-2(3H)-one;5-Fluoro-3-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one;3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-fluoro-1,3-benzoxazol-2(3H)-one;3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(methyloxy)-1,3-benzoxazol-2(3H)-one;3-{1-[trans-4-(Ethyloxy)cyclohexyl]-4-piperidinyl}-5-methyl-1,3-benzoxazol-2(3H)-one;4-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-2H-1,4-benzoxazin-3(4H)-one;3-[1-(cis-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;6-Methyl-1-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-dihydro-2H-indol-2-one;3-{1-[trans-4-Ethoxy-1-methylcyclohexyl]-4-piperidlinyl}-7-fluoro-5-methyl-1,3-benzoxazol-2(3H)-one;3-{1-[trans-4-Ethoxy-1-methylcyclohexyl]-4-piperidinyl}-6,7-difluoro-5-methyl-1,3-benzoxazol-2(3H)-one;5-Methyl-3-{1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one;3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5,7-difluoro-1,3-benzoxazol-2(3H)-one;3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-[(trifluoromethyl)oxy]-1,3-benzoxazol-2(3H)-one;3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5,6-difluoro-1,3-benzoxazol-2(3H)-one;3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-one;6-Methyl-1-{1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl}-1,3-dihydro-2H-indol-2-one;3-{1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinyl▾-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;1-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-6-methyl-1,3-dihydro-2H-indol-2-one;3-{1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one;1-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-7-methyl-3,4-dihydro-2(1H)-quinolinone;3,3,6-Trimethyl-1-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-dihydro-2H-indol-2-one;6-Methyl-1-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-indol-2-one;3-{1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-5-[(trifluoromethyl)sulfonyl]-1,3-benzoxazol-2(3H)-one;6-Methyl-3-{1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinyl}-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one;6-Methyl-5-(methylsulfonyl)-3-{1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one;5-Methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbonitrile;5-(Difluoromethoxy)-3-{1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-1,3-benzoxazol-2(3H)-one;5-Methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one;3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(methyloxy)-1,3-benzoxazol-2(3H)-one;3-(1-{trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexyl}-4-piperidinyl)-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one;3-(1-{trans-1-Methyl-4-[(1-methylethyl)oxy]cyclohexyl}-4-piperidinyl)-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one;3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-one;6-Fluoro-5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]-oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one;7-Fluoro-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;7-Fluoro-5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one;6-Fluoro-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one;3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-[(methyloxy)methyl]-1,3-benzoxazol-2(3H)-one;1-[1-(trans-1-Methyl-4-[2-(methoxyethoxy)cyclohexyl]-4-piperidinyl]-6-(methoxymethyl)-1,3-dihydro-2H-indol-2-one;3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carboxamide;3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carboxamide;5-Acetyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one;3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-[N-(methyloxy)ethanimidoyl]-1,3-benzoxazol-2(3H)-one;1-[1-(trans-4-{2-Methoxyethoxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile;1-[1-(cis-4-{2-Methoxyethoxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile;3-{1-[trans-4-(Ethyloxy)cyclohexyl]-4-piperidinyl}-5-fluoro-1,3-benzoxazol-2(3H)-one;and3-{1-[trans-4-(Ethyloxy)-1-methylcyclohexyl]-4-piperidinyl}-5-methyl[1,3]oxazolo[4,5-b]pyridin-2(3H)-one;and salts thereof.
 7. A method as claimed in claim 1 wherein thepsychotic disorder is schizophrenia, cognitive impairment or Alzheimer'sdisease.
 8. A method as claimed in claim 1 wherein the mammal is ahuman.